AU2021415745A1 - Transition metal complex containing tetradentate nitrogen donor ligand and electrochemical biosensor comprising same - Google Patents
Transition metal complex containing tetradentate nitrogen donor ligand and electrochemical biosensor comprising same Download PDFInfo
- Publication number
- AU2021415745A1 AU2021415745A1 AU2021415745A AU2021415745A AU2021415745A1 AU 2021415745 A1 AU2021415745 A1 AU 2021415745A1 AU 2021415745 A AU2021415745 A AU 2021415745A AU 2021415745 A AU2021415745 A AU 2021415745A AU 2021415745 A1 AU2021415745 A1 AU 2021415745A1
- Authority
- AU
- Australia
- Prior art keywords
- chemical formula
- transition metal
- metal complex
- ghmatters
- ligand
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003446 ligand Substances 0.000 title claims abstract description 79
- 229910052723 transition metal Inorganic materials 0.000 title claims abstract description 52
- 150000003624 transition metals Chemical class 0.000 title claims abstract description 52
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229910052757 nitrogen Inorganic materials 0.000 title claims abstract description 16
- 150000002500 ions Chemical class 0.000 claims description 68
- 239000000126 substance Substances 0.000 claims description 65
- 230000027756 respiratory electron transport chain Effects 0.000 claims description 37
- 108090000854 Oxidoreductases Proteins 0.000 claims description 30
- 102000004316 Oxidoreductases Human genes 0.000 claims description 30
- 229920000642 polymer Polymers 0.000 claims description 28
- 102000004190 Enzymes Human genes 0.000 claims description 24
- 108090000790 Enzymes Proteins 0.000 claims description 24
- 229910052762 osmium Inorganic materials 0.000 claims description 19
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 claims description 16
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 claims description 16
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims description 16
- 150000002907 osmium Chemical class 0.000 claims description 15
- 150000002391 heterocyclic compounds Chemical class 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- VWWQXMAJTJZDQX-UYBVJOGSSA-N flavin adenine dinucleotide Chemical compound C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1CO[P@](O)(=O)O[P@@](O)(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C2=NC(=O)NC(=O)C2=NC2=C1C=C(C)C(C)=C2 VWWQXMAJTJZDQX-UYBVJOGSSA-N 0.000 claims description 8
- 235000019162 flavin adenine dinucleotide Nutrition 0.000 claims description 8
- 239000011714 flavin adenine dinucleotide Substances 0.000 claims description 8
- 229940093632 flavin-adenine dinucleotide Drugs 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 125000005647 linker group Chemical group 0.000 claims description 7
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 claims description 5
- 150000003863 ammonium salts Chemical class 0.000 claims description 5
- 239000012472 biological sample Substances 0.000 claims description 5
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- SMSLWFZHCONMGQ-UHFFFAOYSA-N 2-(1,3-thiazol-2-yl)-1,3-thiazole Chemical compound C1=CSC(C=2SC=CN=2)=N1 SMSLWFZHCONMGQ-UHFFFAOYSA-N 0.000 claims description 4
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 4
- 101710088194 Dehydrogenase Proteins 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 4
- 229910052742 iron Inorganic materials 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 229910052707 ruthenium Inorganic materials 0.000 claims description 4
- 108090000371 Esterases Proteins 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000000033 alkoxyamino group Chemical group 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000005276 alkyl hydrazino group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 3
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 3
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 3
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims description 3
- 229910052741 iridium Inorganic materials 0.000 claims description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 150000001923 cyclic compounds Chemical class 0.000 claims description 2
- PFCMCBTZGOMQIN-UHFFFAOYSA-N indeno[1,2-d]pyridazin-1-one Chemical compound C1=CC=C2C3=CN=NC(=O)C3=CC2=C1 PFCMCBTZGOMQIN-UHFFFAOYSA-N 0.000 claims description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
- 229940101270 nicotinamide adenine dinucleotide (nad) Drugs 0.000 claims description 2
- MMXZSJMASHPLLR-UHFFFAOYSA-N pyrroloquinoline quinone Chemical compound C12=C(C(O)=O)C=C(C(O)=O)N=C2C(=O)C(=O)C2=C1NC(C(=O)O)=C2 MMXZSJMASHPLLR-UHFFFAOYSA-N 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 100
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 82
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 81
- 101100425892 Danio rerio tpma gene Proteins 0.000 description 75
- 101150048952 TPM-1 gene Proteins 0.000 description 75
- 238000006243 chemical reaction Methods 0.000 description 62
- 239000012153 distilled water Substances 0.000 description 58
- 239000000243 solution Substances 0.000 description 58
- 239000011521 glass Substances 0.000 description 56
- 239000000047 product Substances 0.000 description 56
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- 238000010992 reflux Methods 0.000 description 42
- 239000008103 glucose Substances 0.000 description 37
- 238000003756 stirring Methods 0.000 description 37
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 36
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 36
- 230000002829 reductive effect Effects 0.000 description 34
- 239000000203 mixture Substances 0.000 description 32
- -1 preferably Chemical class 0.000 description 32
- 239000007858 starting material Substances 0.000 description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 29
- 239000008280 blood Substances 0.000 description 29
- 210000004369 blood Anatomy 0.000 description 29
- 239000002904 solvent Substances 0.000 description 25
- 229940088598 enzyme Drugs 0.000 description 22
- 239000010410 layer Substances 0.000 description 22
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 21
- 239000002244 precipitate Substances 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- 238000002484 cyclic voltammetry Methods 0.000 description 20
- 238000004821 distillation Methods 0.000 description 19
- 239000003456 ion exchange resin Substances 0.000 description 19
- 229920003303 ion-exchange polymer Polymers 0.000 description 19
- 239000011347 resin Substances 0.000 description 19
- 229920005989 resin Polymers 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 229910052786 argon Inorganic materials 0.000 description 18
- 239000012300 argon atmosphere Substances 0.000 description 18
- 150000001768 cations Chemical class 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- 239000007789 gas Substances 0.000 description 18
- 239000011259 mixed solution Substances 0.000 description 18
- 239000012047 saturated solution Substances 0.000 description 18
- 239000012265 solid product Substances 0.000 description 18
- 230000033116 oxidation-reduction process Effects 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 108010050375 Glucose 1-Dehydrogenase Proteins 0.000 description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 239000003960 organic solvent Substances 0.000 description 11
- 239000012141 concentrate Substances 0.000 description 10
- 239000002274 desiccant Substances 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 235000017550 sodium carbonate Nutrition 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 108010015776 Glucose oxidase Proteins 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 239000004366 Glucose oxidase Substances 0.000 description 8
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 8
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 8
- SRBXXQDKBKTWOC-UHFFFAOYSA-J diazanium;hexachloroosmium(2-) Chemical compound [NH4+].[NH4+].[Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[Os+4] SRBXXQDKBKTWOC-UHFFFAOYSA-J 0.000 description 8
- 229940116332 glucose oxidase Drugs 0.000 description 8
- 235000019420 glucose oxidase Nutrition 0.000 description 8
- 229910052709 silver Inorganic materials 0.000 description 8
- 239000004332 silver Substances 0.000 description 8
- KXZQYLBVMZGIKC-UHFFFAOYSA-N 1-pyridin-2-yl-n-(pyridin-2-ylmethyl)methanamine Chemical compound C=1C=CC=NC=1CNCC1=CC=CC=N1 KXZQYLBVMZGIKC-UHFFFAOYSA-N 0.000 description 7
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 125000006575 electron-withdrawing group Chemical group 0.000 description 7
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000012279 sodium borohydride Substances 0.000 description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000013077 target material Substances 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 6
- 229910021607 Silver chloride Inorganic materials 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 239000002562 thickening agent Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 239000005977 Ethylene Substances 0.000 description 5
- HLWYHRSTHMBVFV-UHFFFAOYSA-N ethyl 2-[(dipyridin-2-ylmethylamino)methyl]pyridine-4-carboxylate Chemical compound CCOC(C1=CC(CNC(C2=NC=CC=C2)C2=NC=CC=C2)=NC=C1)=O HLWYHRSTHMBVFV-UHFFFAOYSA-N 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- BOOZMUQOMHKQCS-UHFFFAOYSA-N tripyridin-2-ylmethanamine Chemical compound C=1C=CC=NC=1C(C=1N=CC=CC=1)(N)C1=CC=CC=N1 BOOZMUQOMHKQCS-UHFFFAOYSA-N 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- MUUDQLHCIAOWPR-UHFFFAOYSA-N diethyl pyridine-2,4-dicarboxylate Chemical compound CCOC(=O)C1=CC=NC(C(=O)OCC)=C1 MUUDQLHCIAOWPR-UHFFFAOYSA-N 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 4
- 229940081066 picolinic acid Drugs 0.000 description 4
- 238000006479 redox reaction Methods 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- GBMRUSRMPOUVEK-UHFFFAOYSA-N (4-methoxypyridin-2-yl)methanol Chemical compound COC1=CC=NC(CO)=C1 GBMRUSRMPOUVEK-UHFFFAOYSA-N 0.000 description 3
- PBDFBZPTRXMFBL-UHFFFAOYSA-N 2-(chloromethyl)-4-methoxypyridine;hydrochloride Chemical compound Cl.COC1=CC=NC(CCl)=C1 PBDFBZPTRXMFBL-UHFFFAOYSA-N 0.000 description 3
- DENUXIGZQGZLCB-UHFFFAOYSA-N 2-(chloromethyl)pyridine-4-carbonitrile Chemical compound ClCC1=CC(C#N)=CC=N1 DENUXIGZQGZLCB-UHFFFAOYSA-N 0.000 description 3
- QYZAHCKDLDXPKU-UHFFFAOYSA-N 2-(hydroxymethyl)pyridine-4-carboxamide Chemical compound NC(=O)C1=CC=NC(CO)=C1 QYZAHCKDLDXPKU-UHFFFAOYSA-N 0.000 description 3
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 3
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 3
- RPHHYRNGCJYQSP-UHFFFAOYSA-N 4-bromopyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC(Br)=CC=N1 RPHHYRNGCJYQSP-UHFFFAOYSA-N 0.000 description 3
- 102000007698 Alcohol dehydrogenase Human genes 0.000 description 3
- 108010021809 Alcohol dehydrogenase Proteins 0.000 description 3
- 108010025188 Alcohol oxidase Proteins 0.000 description 3
- 102100035687 Bile salt-activated lipase Human genes 0.000 description 3
- 108010015428 Bilirubin oxidase Proteins 0.000 description 3
- 108010089254 Cholesterol oxidase Proteins 0.000 description 3
- 102000016901 Glutamate dehydrogenase Human genes 0.000 description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 3
- 235000019502 Orange oil Nutrition 0.000 description 3
- MLCPWIJYAMXLDB-UHFFFAOYSA-N [2-[(dipyridin-2-ylmethylamino)methyl]pyridin-4-yl]methanol Chemical compound OCC1=CC(CNC(C2=NC=CC=C2)C2=NC=CC=C2)=NC=C1 MLCPWIJYAMXLDB-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 3
- 229910052737 gold Inorganic materials 0.000 description 3
- 239000010931 gold Substances 0.000 description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000010502 orange oil Substances 0.000 description 3
- 230000005298 paramagnetic effect Effects 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- LWGRHHZXVIERGZ-UHFFFAOYSA-N (4-methoxypyridin-2-yl)carbamic acid Chemical compound COC1=CC(=NC=C1)NC(=O)O LWGRHHZXVIERGZ-UHFFFAOYSA-N 0.000 description 2
- VGUWFGWZSVLROP-UHFFFAOYSA-N 1-pyridin-2-yl-n,n-bis(pyridin-2-ylmethyl)methanamine Chemical compound C=1C=CC=NC=1CN(CC=1N=CC=CC=1)CC1=CC=CC=N1 VGUWFGWZSVLROP-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- LJCNDNBULVLKSG-UHFFFAOYSA-N 2-aminoacetic acid;butane Chemical compound CCCC.CCCC.NCC(O)=O LJCNDNBULVLKSG-UHFFFAOYSA-N 0.000 description 2
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 2
- CMMURVLHXMNTHY-UHFFFAOYSA-N 4-methylpyridine-2-carboxylic acid Chemical compound CC1=CC=NC(C(O)=O)=C1 CMMURVLHXMNTHY-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 101000950981 Bacillus subtilis (strain 168) Catabolic NAD-specific glutamate dehydrogenase RocG Proteins 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229920002491 Diethylaminoethyl-dextran Polymers 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 108010073450 Lactate 2-monooxygenase Proteins 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 108010055297 Sterol Esterase Proteins 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 235000011148 calcium chloride Nutrition 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000002041 carbon nanotube Substances 0.000 description 2
- 229910021393 carbon nanotube Inorganic materials 0.000 description 2
- 229920002301 cellulose acetate Polymers 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000002848 electrochemical method Methods 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000012212 insulator Substances 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229950006238 nadide Drugs 0.000 description 2
- 229920002006 poly(N-vinylimidazole) polymer Polymers 0.000 description 2
- 239000004417 polycarbonate Substances 0.000 description 2
- 229920000139 polyethylene terephthalate Polymers 0.000 description 2
- 239000005020 polyethylene terephthalate Substances 0.000 description 2
- 229920002635 polyurethane Polymers 0.000 description 2
- 239000004814 polyurethane Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 239000011241 protective layer Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920002379 silicone rubber Polymers 0.000 description 2
- 239000004945 silicone rubber Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000006276 transfer reaction Methods 0.000 description 2
- YFSUTJLHUFNCNZ-UHFFFAOYSA-M 1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-heptadecafluorooctane-1-sulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F YFSUTJLHUFNCNZ-UHFFFAOYSA-M 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- STMDPCBYJCIZOD-UHFFFAOYSA-N 2-(2,4-dinitroanilino)-4-methylpentanoic acid Chemical compound CC(C)CC(C(O)=O)NC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O STMDPCBYJCIZOD-UHFFFAOYSA-N 0.000 description 1
- JPMRGPPMXHGKRO-UHFFFAOYSA-N 2-(chloromethyl)pyridine hydrochloride Chemical compound Cl.ClCC1=CC=CC=N1 JPMRGPPMXHGKRO-UHFFFAOYSA-N 0.000 description 1
- DYHMIVKBJSIOCH-UHFFFAOYSA-N 4-methoxypyridine-2-carboxamide Chemical compound COC1=CC=NC(C(N)=O)=C1 DYHMIVKBJSIOCH-UHFFFAOYSA-N 0.000 description 1
- UELRAKDBDJRXST-UHFFFAOYSA-M 4-methoxypyridine-2-carboxylate Chemical compound COC1=CC=NC(C([O-])=O)=C1 UELRAKDBDJRXST-UHFFFAOYSA-M 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 108010024957 Ascorbate Oxidase Proteins 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 description 1
- 108700023156 Glutamate dehydrogenases Proteins 0.000 description 1
- 229910003556 H2 SO4 Inorganic materials 0.000 description 1
- 101000632319 Homo sapiens Septin-7 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical class CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 229920000557 Nafion® Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000004642 Polyimide Substances 0.000 description 1
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 102100027981 Septin-7 Human genes 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 102220523035 Transmembrane protein 44_H24N_mutation Human genes 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- BKRKYEFQSANYGA-UHFFFAOYSA-N bromo-methyl-triphenyl-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Br)(C=1C=CC=CC=1)(C)C1=CC=CC=C1 BKRKYEFQSANYGA-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- YAGKRVSRTSUGEY-UHFFFAOYSA-N ferricyanide Chemical class [Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] YAGKRVSRTSUGEY-UHFFFAOYSA-N 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical class [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 235000012209 glucono delta-lactone Nutrition 0.000 description 1
- 229960003681 gluconolactone Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- ARRNBPCNZJXHRJ-UHFFFAOYSA-M hydron;tetrabutylazanium;phosphate Chemical compound OP(O)([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC ARRNBPCNZJXHRJ-UHFFFAOYSA-M 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229940030980 inova Drugs 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000005040 ion trap Methods 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- MJIVRKPEXXHNJT-UHFFFAOYSA-N lutidinic acid Chemical compound OC(=O)C1=CC=NC(C(O)=O)=C1 MJIVRKPEXXHNJT-UHFFFAOYSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 150000002908 osmium compounds Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229920001721 polyimide Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical compound OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- OVYTZAASVAZITK-UHFFFAOYSA-M sodium;ethanol;hydroxide Chemical compound [OH-].[Na+].CCO OVYTZAASVAZITK-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003866 tertiary ammonium salts Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- FHCPAXDKURNIOZ-UHFFFAOYSA-N tetrathiafulvalene Chemical class S1C=CSC1=C1SC=CS1 FHCPAXDKURNIOZ-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
- C07F15/002—Osmium compounds
- C07F15/0026—Osmium compounds without a metal-carbon linkage
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/001—Enzyme electrodes
- C12Q1/002—Electrode membranes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/001—Enzyme electrodes
- C12Q1/004—Enzyme electrodes mediator-assisted
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/001—Enzyme electrodes
- C12Q1/005—Enzyme electrodes involving specific analytes or enzymes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/26—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving oxidoreductase
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- General Engineering & Computer Science (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Biophysics (AREA)
- Analytical Chemistry (AREA)
- Physics & Mathematics (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Pyridine Compounds (AREA)
- Hybrid Cells (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
- Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to: a novel transition metal complex containing a tetradentate nitrogen donor ligand, which can be used in various devices including electrochemical sensors; and a device comprising same, preferably an electrochemical sensor.
Description
Cross-reference to related application(s) The present application claims the benefit of the priority based on Korean Patent Application No. 10-2020-0189139 filed on December 31, 2020, and the entire contents disclosed in the document of the corresponding Korean patent application are incorporated as a part of the present description. The present invention relates to a transition metal complex comprising a useful tetradentate nitrogen donor ligand as an electron transfer mediator and an electrochemical biosensor comprising the same.
Diabetes is disease that occurs when a high blood glucose level is maintained for a long time, and causes complications such as cardiovascular disease, stroke, kidney disease and the like. In response to the high blood glucose level, a process of reducing the blood glucose level by insulin injection, but if insulin is over-injected, hypoglycemia may occur, which may lead to shock or death. To prevent this, it is essential for diabetic patients to continuously measure the blood glucose concentration in the body using a blood glucose measuring sensor for the purpose of maintaining an appropriate blood glucose level. Recently, a blood glucose sensor to which a Continuous Glucose Monitoring System (CGMS) is applied has been studied and commercialized considerably. The CGMS sensor is a device which is inserted into subcutaneous tissue and continuously measures the glucose concentration through intercellular fluid. In case of finger blood collecting method, it is difficult to confirm the exact change in the blood glucose level by blood glucose measurement
20004399_1 (GHMatters) P122101.AU
~ 6 times a day, whereas the CGMS has an advantage of checking the change and tendency of the blood glucose level in a day. Through this, patients can quickly recognize hyperglycemia or hypoglycemia, and the ability to manage blood glucose can be further improved. A biosensor refers to a device that selectively detects a biological sample and converts it into a specific signal. In particular, an enzyme-based biosensor using an electrochemical method is preferred because of its improved selectivity by the enzyme, as well as possible miniaturization and accuracy of measurement. The blood glucose biosensor using an electrochemical method is divided into first-generation and second-generation methods. The first-generation blood glucose sensor was first developed by Clark and Lyon, and is a method of measuring a blood glucose level through a change in the reduced oxygen concentration and concentration of generated hydrogen peroxide through an oxidation reduction reaction of the enzyme, and the second-generation blood glucose sensor is a method of transferring electrons generated by an oxidation-reduction reaction of the enzyme to an electrode through an electron transfer mediator. The second-generation sensor has many advantages compared to the first-generation sensor in that there is less error depending on the oxygen concentration and the electron transfer reaction by a mediator is efficient and fast. For this reason, the second-generation sensor method comprising an electron transfer mediator is being applied to the CGMS blood glucose sensor. An electrochemical enzyme-based blood glucose biosensor is generally composed of an enzyme, an electron transfer mediator, and an electrode. At first, glucose is oxidized to gluconolactone by the enzyme, and then the reduced enzyme is oxidized and donates electrons to the electron transfer mediator. Then, the reduced mediator passes through a process of transferring electrons to the electrode as it is oxidized. From this series of processes, the blood glucose level can be confirmed by an electrical signal.
Enzymes applied to the blood glucose sensor generally include glucose oxidase (GOx) and glucose dehydrogenase (GDH). GOx has been widely applied in the blood glucose sensor because it selectively oxidizes glucose and has a low cost and high stability. However, since GOx is greatly affected by oxygen in the oxidation process, it is known that the GOx based blood glucose sensor has an error in measuring the blood glucose level higher than the actual level in a high altitude or low atmospheric pressure region. Unlike the GOx, GDH is
20004399_1 (GHMatters) P122101.AU characterized in that it can selectively oxidize glucose independently of oxygen concentration. In particular, GDH comprising FAD (flavin adenine dinucleotide) has a great advantage in being applied to the blood glucose sensor because it is not affected by oxygen and has excellent thermal stability. However, since a thick protein membrane surrounds the FAD active site, it is difficult for GDH to directly transfer electrons to the electrode surface. In order to solve this problem, the role of the electron transfer mediator, which facilitates the electron transfer reaction between the enzyme and electrode surface, is very important. Electrochemical properties of the electron transfer mediator are key factors that can affect rapid electron transfer and selectivity and sensitivity in the blood glucose sensor. Interference of interfering substances in a living body can be avoided according to the potential of the mediator, and redox shuttling, a phenomenon in which the mediator generates an error current through repeated oxidation-reduction reactions between adjacent electrodes, can be thermodynamically avoided. Therefore, it is ideal that the electron transfer mediator has a reasonably low oxidation-reduction potential (-0.2V ~ OV vs Ag/AgCl) to perform an effective function. In addition, both oxidizing species and reducing species must be chemically stable and non-toxic in a body. The electron transfer mediator that has been studied a lot so far includes ferrocene derivatives, ferricyanide, tetrathiafulvalene, transition metal complexes, and the like. Recently, complexes with iron, ruthenium and osmium as a central metal have been studied a lot as the electron transfer mediator, but there is still a need for a new electron transfer mediator which has high efficiency, is stable and has no toxicity in a body. Under this background, the present inventors have repeated studies on a transition metal complex useful as an electron transfer mediator for an electrochemical biosensor, and as a result, they have confirmed that when tris-2-pyridylmethylamine (tris(2 pyridylmethyl)amine, TPMA) is introduced as a tetradentate ligand, it exhibits exceptionally high stability compared to conventional monodentate or bidentate ligands, and a transition metal complex prepared therefrom can be easily synthesized and shows stable electrochemical properties, thereby completing the present invention.
20004399_1 (GHMatters) P122101.AU
An object of the present invention is to provide a novel transition metal complex for an electron transfer mediator comprising a tetradentate nitrogen donor ligand.
Another object of the present invention is to provide an electrochemical biosensor comprising a redox polymer comprising the transition metal complex. Other object of the present invention is to provide a method for preparation of the transition metal complex.
According to one aspect of the present invention, a transition metal complex comprising a tetradentate nitrogen donor ligand, useful as an electron transfer mediator can be provided. According to one aspect of the present invention, a method for preparing the transition metal complex can be provided. According to one aspect of the present invention, a device comprising the transition metal complex as an electron transfer mediator can be provided. According to one aspect of the present invention, a sensing layer for an electrochemical biosensor comprising an enzyme capable of redoxing a liquid biological sample; and the transition metal complex as an electron transfer mediator can be provided.
The transition metal complex comprising a tetradentate nitrogen donor ligand according to the present invention excellently improves the performance of an electrochemical sensor when used for an electrochemical sensor.
FIG. 1 is a drawing which discloses various synthesis methods to prepare tetradentate ligands for preparing the transition metal complex of the present invention.
20004399_1 (GHMatters) P122101.AU
FIG. 2 is a reaction formula showing the synthesis method of the
[Os(TPMA)C 2]*(PF6-) complex and various derivatives which can be synthesized therefrom. FIG. 3 is a drawing which shows the crystal structure of [Os(TPMA)Cl 2]*(PF6-). FIG. 4 is a reaction formula showing the synthesis method of the
[Os(TPMA)(L)i~ 2 ]"(PF6-)n complex and various derivatives which can be synthesized therefrom. FIG. 5 is a drawing which shows the change in the mass signal confirmed on ESI-MS of the hydroxymethyl TPMA osmium complex. FIG. 6 is a graph showing CV data of [Os(TPMA)Cl 2 ]*(X-)(18). FIGs. 7a to 7c are drawings which show the structures and oxidation-reduction potentials of the osmium complexes based on TPMA. FIGs. 8a and 8b are graphs comparing the potential values by cyclic voltammetry of the [Os(TPMA)Cl2]*(PF6-) complexes depending on the substituent. FIG. 8a is a graph comparing to the complexes with EDG (18, 21, 23), and FIG. 8b is a graph comparing to the complexes with EWG (18, 19, 20, 22). In order to compare the potential values of the complexes regardless of the concentration, the current value was corrected to 18, and measured by injection at 10 mV/s in 0.1 M TPMP in CH3CN solution. FIG. 9 is a graph showing CV data of the [Os(TPMA)C 2]*(PF6-) Complex (19). FIG. 10 is a graph showing CV data of the [Os(TPMA)Cl 2]*(PF6-) Complex (20). FIG. 11 is a graph showing CV data of the [Os(TPMA)Cl 2]*(PF6-) Complex (21). FIG. 12 is a graph showing CV data of the [Os(TPMA)Cl 2]*(PF6-) Complex (22). FIG. 13 is a graph showing CV data of the [Os(TPMA)Cl 2]*(PF6-) Complex (23). FIG. 14 is a graph showing CV data of the [Os(TPMA)(L)~2]"(PF6-)n Complex (24). FIG. 15 is a graph showing CV data of the [[Os(TPMA)(L)i~2]"(PF6-)n Complex (25). FIG. 16 is a graph showing CV data of the [Os(TPMA)(L)~2]"(PF6-)n Complex (26). FIG. 17 is a graph showing CV data of the [Os(TPMA)(L)~2]"(PF6-)n Complex (27). FIG. 18 is a graph showing CV data of the [Os(TPMA)(L)~2]"(PF6-)n Complex (28). FIG. 19 is a graph showing CV data of the [Os(TPMA)(L)~2]"(PF6-)n Complex (29). FIG. 20 is a graph showing CV data of the [Os(TPMA)(L)~2]"(PF6-)n Complex (30). FIG. 21 is a graph showing CV data of the [Os(TPMA)(L)i~2]"(PF6-)n Complex (31). FIG. 22is a graph showing CV data of the [Os(TPMA)(L)~2]"(PF6-)n Complex (32). FIG. 23 is a graph showing CV data of the [Os(TPMA)(L)~2]"(PF6-)n Complex (33).
20004399_1 (GHMatters) P122101.AU
FIG. 24 is a graph showing CV data of the [Os(TPMA)(L)~ ]"*(PF6j)n 2 Complex (34). FIG. 25 is a graph showing CV data of the [Os(TPMA)(L)~ ]"*(PF6j)n 2 Complex (35).
As one aspect, the present invention provides a transition metal complex comprising a tetradentate nitrogen donor ligand useful as an electron transfer mediator. As one embodiment, the transition metal complex may be represented by Chemical formula 1 or 2 below.
[Chemical formula 1]
R1 -m
N R3
N" N --NnX N /
N Lmn2
_R2
[Chemical formula 2]
R1m
N R3
NN nX
N Lb Lb
In the Chemical formula 1 or Chemical formula 2, M may be one selected from the group consisting of Fe, Co, Ru, Os, Rh and Ir; and
20004399_1 (GHMatters)P122101.AU
Ca, Cb, Cc are heterocyclic compounds comprising one or more nitrogen atoms, and are preferably linked to an amine group and a methylene group at the position 2 of the cyclic compound; and L" and L2 are monodentate ligands coordinated each independently; and L is a bidentate ligand comprising nitrogen or oxygen; and m is a negative charge or positive charge showing -1 ~ -5 or 1 ~ 5; and R1, R2 and R 3 are each independently a structure composed of a linker into which a reactive group capable of linking to a polymer is introduced; and X is a counter ion; and n means the number of counter ions, and is 1 - 5. As one embodiment, the transition metal complex may comprise a tetradentate ligand represented by Chemical formula 3 below.
[Chemical formula 3] N4
NR2 N N N CD
R3 In the formula, Ca, Cb and Cc are each independently a heterocyclic compound comprising one or more nitrogen atoms; and R1, R2 and R 3 are each independently a linker into which a reactive group capable of linking to a polymer is introduced, or an electron donating group (EDG) or electron withdrawing group (EWG) for controlling an oxidation/reduction potential. In one example, the tetradentate ligand of Chemical formula 3 above may be one of ligands having the following structures:
200043991 (GHMatters) P122101.AU
Et0 O 0
N' EtO 0 EtO' 0 ' HOt N Et N QEt N HO N N 'N N 0 N6
10 11 12 13
H H2NN N N CN EtO N OEt
N NN 'IN N N N N 00
15 16 17 14 15 , ,and
Preferably, the heterocyclic compound may be linked to an amine group and a methylene group at position 2, and three nitrogens of the three hetero rings and one nitrogen at the center connecting the three hetero rings to each other may be connected to the transition metal M. Specifically, the RI, R2 and R3 of Chemical formulas 1 to 3 above may be each independently -H; -F; -Cl; -Br; -I; -N02; -CN; -CO 2 H; -SO 3 H; -NHNH 2; -SH; -OH; -NH 2; CH 2 OH; -CONHCH 2CH 2NH 2 ; or substituted or unsubstituted alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxy, alkylamino, dialkylamino, alkanylamino, arylcarboxyamido, hydrazino, alkylhydrazino, hydroxyamino, alkoxyamino, alkylthio, alkenyl, aryl or alkyl. Specifically, the L" and L2are monodentate ligands, and may be each independently -H, -F, -Cl, -Br, -I, -N02, -NCCH 3, -CO, -OH 2 , -NH3 or a heterocyclic compound comprising one or more nitrogen atoms. Specifically, the Ire Lb- Lb may be catechol, acetylacetone, 2-picolinic acid, 2 pyridinecarboxamide, 2,2-bipyridine or 2,2-bithiazole. As one specific aspect, the heterocyclic compound may be one or more kinds selected from the group consisting of imidazole, pyridine, pyrimidine, pyrazole, isoxazole, oxazole, thiazole, benzothiazole, benzimidazole, benzoxazole and diazafluorenone.
As one specific aspect, when the alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxy, alkylamino, dialkylamino, alkanylamino, arylcarboxyamido, hydrazino, alkylhydrazino, hydroxyamino, alkoxyamino, alkylthio, alkenyl, aryl, alkyl and 3
200043991 (GHMatters) P122101.AU ring heterocyclic ring are substituted, they may be substituted with one or more, preferably, 1 to 3 selected from the group consisting of -F, -Cl, -Br, -I, -OH, oxo, alkyl groups having 1 to 3 carbon atoms and alkoxy groups having 1 to 3 carbon atoms.
As one specific aspect, the transition metal complex of Chemical formula 1 or 2 according to the present invention may be one of the transition metal complexes shown in Table 1 below:
[Table t]
Complex Chemical structure of transition metal complexes number
18 1+
19 EtO 0 - -1+ 0 N N . I..OEt Ns (X-)
20 EtO 0
- -1+
N N N ( NOs \ CI CI
20004399_1 (GHMatters)P122101.AU
21 OH
- ---- -1+
s N N N (X-)
22 H H 2N N - -1+
23 OMe - -- -1+
N OMe
N" Os( 2/N\
24 -1+/2+
N 7N N _zr, Os, H Wl1 /N\ NH 0 N_
OMe
20004399_1 (GHMatters)P122101.AU
25 -2+
N N- (X-)2 N N N N
26 -'
27 - N' 1+
N~ 0
Br 28 1+
N (X-) N 2N\ 0 ~
20004399_1 (GHMatters)P122101.AU
29 - 1+
N OsN (X-) / 0
N<'
30 1+/2+
N 0 2N'N\ 0
31 OH
- 1+
((X-) N"" N' Os N N_ 0
32 OH
( N (X) /N\ 0 N~
20004399_1 (GHMatters)P122101.AU
33 H H 2N N 0 1+/2+
N' N 0
34 H H 2N N 2+
Os (X-) 2 /N N N \ NI \ N N
35 OMe -2+
N OMe
NA (X-)2 Os
As another aspect, the present invention provides a method for preparation of the transition metal complex useful as an electron transfer mediator. The transition metal complex useful as an electron transfer mediator according to the present invention may be prepared by a salt, preferably, osmium salt, of the transition metal. In one specific embodiment, the salt of the transition metal may be an ammonium salt of the halogenated transition metal of Chemical formula 4 below,
20004399_1 (GHMatters)P122101.AU
[Chemical formula 4]
[(NH 4) 2MX 6]
In the formula, M may be one selected from the group consisting of Fe, Co, Ru, Os, Rh and Ir; and X is F, Cl, Br, or I. Preferably, the ammonium salt of the halogenated transition metal of Chemical formula 4 may be ammonium hexachloroosmate of Chemical formula 5, and this is commercially available.
[Chemical formula 5]
[(NH 4) 2 0sCl]
In one example, the method for preparation of the transition metal complex according to the present invention may synthesize it using a tris-pyridinemethylamine-based ligand and an ammonium salt of the halogenated transition metal. As a specific embodiment, in case of the complex comprising osmium, it may comprise the following steps: a) introducing a tetradentate tris-pyridinemethylamine-based ligand represented by Chemical formula 3 into an ammonium salt of halogenated osmium of Chemical formula 5, to synthesize an osmium complex of Chemical formula 6; and b) introducing one kind or 2 kinds of monodentate ligands or bidentate ligands selected from the group consisting of N-N ligands, N-ligands, N-0 ligands and 0-0 ligands into the osmium complex of Chemical formula 6. As one embodiment, the transition metal complex may comprise a tetradentate ligand represented by Chemical formula 3 below.
[Chemical formula 3]
R1 N b CC
R3 In the formula, Ca, Cb and Cc are each independently a heterocyclic compound comprising one or more nitrogen atoms; and 200043991 (GHMatters) P122101.AU
R1, R2 and R3 are each independently a linker into which a reactive group capable of linking to a polymer is introduced.
The first step is a step of synthesizing in an osmium complex represented by Chemical formula 6 in a trivalent ionic state, by introducing a tris-pyridinemethylamine-based ligand of Chemical formula 3 into an osmium salt of Chemical formula 5 in a tetravalent ionic state.
[Chemical formula 6] N N m
N- Os - CI dX
The second step is a step of synthesizing an osmium complex represented by any one of Chemical formulas 7 to 11 by introducing 1 kind or 2 kinds of monodentate ligands or bidentate ligands selected from the group consisting of N-N ligand, N-ligand, N-0 ligand and -0 ligand into the osmium complex synthesized in the first step. Preferably, in the second step, to the osmium complex of Chemical formula 6 synthesized in the second step, 1 N-N ligand, 2 N ligands, 1 N ligand, 1 N-0 ligand or 10-0 ligand may be introduced.
[Chemical formula 7] - N m
N-Cs -Nd
[Chemical formula 8]
N -- N CdX
[Chemical formula 9]
200043991 (GHMatters) P122101.AU
[Chemical formula 10]
[Chemical formula 11] (N m
N-a -0 d
In one embodiment, the N ligand may be -N02, -NCCH3 , -NH 3 or a heterocyclic compound comprising one or more nitrogen atoms. As one embodiment, the N-N ligand may be 2-pyridinecarboxamide, 2,2'-bipyridine, 2,2'-bithiazole or 2-pyridylmethylamine. As one embodiment, the N-0 ligand may be 2-picolinic acid, 2-aminophenol or 2 hydroxymethylpyridine. As one embodiment, the 0-0 ligand may be catechol or acetylacetone.
The electron transfer mediator transition metal complex according to the present invention plays a role of transferring electrons obtained by reduction (glucose oxidation) of oxidoreductase, and may be used in a redox polymer form which is linked to a polymer matrix corresponding to a polymer backbone such as one or more kinds selected from the group consisting of poly(vinylpyridine) (PVP) or poly(vinylimidazole) (PVI), and poly allyl glycidyl ether (PAGE). Accordingly, one additional aspect of the present invention, relates to a redox polymer comprising the transition metal complex for an electron transfer mediator and a polymer backbone. In one embodiment, the redox polymer may comprise a linker structure which connects the polymer backbone and an organic series electron transfer mediator. 200043991 (GHMatters) P122101.AU
In addition, one additional aspect of the present invention relates to a sensing layer for an electrochemical biosensor comprising an enzyme capable of redoxing a liquid biological sample and an electron transfer mediator comprising the transition metal complex. Oxidoreductase is a generic term for enzymes that catalyze the redox reaction of a living body, and in the present invention, it means a target material to be measured, for example, in case of a biosensor, an enzyme to be reduced by reacting with the target material. The reduced enzyme as above reacts with an electron transfer mediator, and then, the target material is quantified by measuring a signal such as a change in current generated. The oxidoreductase usable in the present invention may be one or more kinds selected from the group consisting of various kinds of dehydrogenase, oxidase, esterase and the like, and depending on the redox or detection target material, an enzyme having the target material as a substrate among enzymes belonging to the enzyme group may be selected and used. More specifically, the oxidoreductase may be one or more kinds selected from the group consisting of glucose dehydrogenase, glutamate dehydrogenase, glucose oxidase, cholesterol oxidase, cholesterol esterase, lactate oxidase, ascorbic acid oxidase, alcohol oxidase, alcohol dehydrogenase, bilirubin oxidase, and the like. On the other hand, the oxidoreductase may comprise a cofactor which plays a role of storing hydrogen stolen by the oxidoreductase from the target material to be measured (for example, target material) together, and for example, it may be one or more kinds selected from the group consisting of flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide (NAD), pyrroloquinoline quinone (PQQ), and the like. For example, when the blood glucose concentration is to be measured, glucose dehydrogenase (GDH) may be used as the oxidoreductase, and the glucose dehydrogenase may be flavin adenine dinucleotide-glucose dehydrogenase (FAD-GDH) comprising FAD as a cofactor, and/or nicotinamide adenine dinucleotide- glucose dehydrogenase comprising FAD-GDH as a cofactor. In a specific embodiment, the usable oxidoreductase may be one or more kinds selected from the group consisting of FAD-GDH (for example, EC 1.1.99.10, etc.), NAD GDH (for example, EC 1.1.1.47, etc.), PQQ-GDH (for example, EC1.1.5.2, etc.), glutamate dehydrogenase (for example, EC 1.4.1.2, etc.), glucose oxidase (for example, EC 1.1.3.4, etc.), cholesterol oxidase (for example, EC 1.1.3.6, etc.), cholesterol esterase (for example, EC 3.1.1.13, etc.), lactate oxidase (for example, EC 1.1.3.2, etc.), ascorbate oxidase (for example, 20004399_1 (GHMatters) P122101.AU
EC 1.10.3.3, etc.), alcohol oxidase (for example, EC 1.1.3.13, etc.), alcohol dehydrogenase (for example, EC 1.1.1.1, etc.), bilirubin oxidase (for example, EC 1.3.3.5, etc.), and the like. Most preferably, the oxidoreductase is glucose dehydrogenase capable of maintaining the activity of 70% or more in a 37°C buffer solution for 1 week. The sensing layer according to the present invention may contain a redox polymer of to 700 parts by weight, for example, 60 to 700 parts by weight, or 30 to 340 parts by weight, based on oxidoreductase 100 parts by weight. The content of the redox polymer may be appropriately adjusted according to the activity of oxidoreductase.
Moreover, the sensing layer according to the present invention may further comprise a carbon nanotube for increasing the membrane performance. Specifically, the carbon nanotube may further increase the performance of the sensing layer as the electron transfer rate is increased when a transition metal complex, particularly, osmium is used together.
In addition, the sensing layer according to the present invention may further comprise a crosslinking agent. On the other hand, the sensing layer according to the present invention may further comprise one or more kinds of additives selected from the group consisting of a surfactant, an aqueous polymer, a tertiary ammonium salt, a fatty acid, a thickener, and the like, for a role of a role of a dispersing agent during reagent dissolution, an adhesive during reagent preparation, a stabilizer for storage for a long period of time, and the like. The surfactant may play a role of distributing the composition evenly on an electrode to be aliquoted in a uniform thickness, when the composition is aliquoted. As the surfactant, one or more kinds selected from the group consisting of Triton X-100, sodium dodecyl sulfate, perfluorooctane sulfonate, sodium stearate, and the like. The reagent composition according to the present invention may contain the surfactant in an amount of 3 to 5 parts by weight, for
example, 10 to 25 parts by weight, based on oxidoreductase 100 parts by weight, so as to appropriately perform the role of evenly distributing the reagent on an electrode to be aliquoted with a uniform thickness when the reagent is aliquoted. For example, when oxidoreductase having an activity of 700 U/mg is used, 10 to 25 parts by weight of a surfactant based on oxidoreductase 100 parts by weight may be contained, and when the
20004399_1 (GHMatters) P122101.AU activity of oxidoreductase is higher than this, the content of the surfactant may be adjusted lower than this. The aqueous polymer is a polymer supporter of a reagent composition, which performs a role of helping stabilization and dispersing of an enzyme. As the aqueous polymer, one or more kinds selected from the group consisting of polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyperfluoro sulfonate, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), carboxy methyl cellulose (CMC), cellulose acetate, polyamide, and the like may be used. The reagent composition according to the present invention, may contain the aqueous polymer of 10 to 70 parts by weight, for example, 30 to parts by weight, based on oxidoreductase 100 parts by weight, in order to sufficiently and appropriately exhibiting a role of helping stabilization and dispersing of oxidoreductase. For example, when oxidoreductase having an activity of 700 U/mg is used, the aqueous polymer of 30 to 70 parts by weight based on oxidoreductase 100 parts by weight may be contained, and when the activity of oxidoreductase is higher than this, the content of the aqueous polymer may be adjusted lower than this. The aqueous polymer may have a weight average molecular weight of about 2,500 g/mol to 3,000,000 g/mol, for example, 5,000 g/mol to 1,000,000 g/mol, so as to effectively perform a role of helping stabilization and dispersing of the supporter and enzyme. The thickener plays a role of strongly attaching a reagent to an electrode. As the thickener, one or more kinds selected from the group consisting of natrosol, diethylaminoethyl-dextran hydrochloride (DEAE-Dextran hydrochloride) and the like may be used. The electrochemical sensor according to the present invention, may contain the thickener in an amount of 10 to 90 parts by weight, for example, 30 to 90 parts by weight, based on oxidoreductase 100 parts by weight, in order to strongly attach the redox polymer according to the present invention to an electrode. For example, when oxidoreductase having an activity of 700 U/mg is used, the thickener of 30 to 90 parts by weight based on oxidoreductase 100 parts by weight may be contained, and when the activity of oxidoreductase is higher than this, the content of the thickener may be adjusted lower than this.
As other aspect, the present invention may be a device, preferably, an insertable device, more specifically, a device insertable into a human body, comprising this organic 20004399_1 (GHMatters) P122101.AU electron transfer mediator. In addition, preferably, the device may be an electrochemical biosensor, more preferably, an electrochemical glucose (blood glucose) sensor. Specifically, there is no limitation on the type of the electrochemical biosensor, but it may be a continuous blood glucose monitoring sensor. As the composition of this continuous blood glucose monitoring sensor, the present invention, may comprise for example, an electrode, an insulator, a substrate, a sensing layer comprising the redox polymer and oxidoreductase, a diffusion layer, a protection layer, and the like. In case of the electrode, two kinds of electrodes such as a working electrode and a counter electrode, and may comprise three kinds of electrodes such as a working electrode, a counter electrode and a reference electrode. In one embodiment, the biosensor according to the present invention may be an electrochemical biosensor produced by applying a reagent composition comprising a redox polymer comprising the organic series electron transfer mediator of Chemical formula 1 and an enzyme capable of redoxing a liquid biological sample, to a substrate having at least two, preferably, two or three electrodes, and drying. For example, in the electrochemical biosensor, a planar electrochemical biosensor, in which a working electrode and a counter electrode are equipped on opposite sides each other, and a sensing layer comprising a redox polymer having the organic series electron transfer mediator according to the present invention is laminated on the working electrode, and an insulator, a diffusion layer and a protective layer are laminated in order on both sides of the substrate equipped with the working electrode and counter electrode, is provided.
As a specific aspect, the substrate may be made of one or more kinds selected from the group consisting of PET (polyethylene terephthalate), PC (polycarbonate) and PI (polyimide). In addition, the working electrode may use a carbon, gold, platinum, silver or silver/silver chloride electrode. Furthermore, in case of an electrochemical biosensor having 2 electrodes, a counter electrode also plays a role of a reference electrode, and therefore, as the counter electrode, a gold, platinum, silver or silver/silver chloride electrode may be used, and in case of an electrochemical biosensor of three electrodes comprising a reference electrode, as the reference electrode, a gold, platinum, silver or silver/silver chloride electrode may be used, and as the counter electrode, a carbon electrode may be used. 20004399_1 (GHMatters) P122101.AU
As the diffusion layer, Nafion, cellulose acetate and silicone rubber may be used, and as the protective layer, silicone rubber, polyurethane, polyurethane-based copolymer and the liker may be used, but not limited thereto. As a non-limited example, in case of two electrodes, the counter electrode also plays a role of the reference electrode, and therefore, silver chloride or silver may be used, and in case of three electrodes, as the reference electrode, silver chloride or silver may be used, and as the counter electrode, a carbon electrode may be used. A specific embodiment of the present invention illustrates a biosensor for measuring glucose as an applicable example of the electrochemical biosensor, but by changing the type of enzyme comprised in the reagent composition of the present invention, it may be applied for a biosensor for quantification of various substances such as cholesterol, lactate, creatinine, hydrogen peroxide, alcohol, amino acid, and glutamate.
Hereinafter, the present invention will be described in more detail by the following examples. However, the following examples illustrate the present invention only, but the content of the present invention is not limited by the following examples.
[Example] Experimental materials Commercially purchased solvents and reagents were used without further purification process. In case of alumina for metal complex purification, neutral alumina of Aldrich was filtered using a 1OmL pipette. For the resin for the chloride counterion exchange of the complex, Dowex 1x4 chloride form, 50-100mesh pf Aldrich was used. 'H-NMR and "C-NMR spectra were obtained using Varian Inova 400 (400 MHz for 'H, 100 MHz for "C). All chemical shifts were determined proportionally to tetramethyl silane peaks (6 0.00) or deuterated chloroform (67.26 for CDCl3 in 'H NMR, 677.16 for CDCl3 in 1 3 C NMR), or deuterated dimethylacetamide (62.50 for DMSO in 'H NMR, 639.52 for DMSO in1 3 C NMR). The mass spectra were obtained by ESI-Iontrap for low resolution and ESI-orbitrap mass spectrometer for high resolution, of LTQ XL model of ThermoFisher Scientific at Sogang University's Organic Chemistry Research Center.
Example 1. Synthesis of TPMA ligands 20004399_1 (GHMatters) P122101.AU
TPMA ligands having various functional groups were synthesized according to the synthetic route shown in FIG. 1. Bis-2-pyridylmethylamine (1) and tris-2-pyridyl methylamine (10) were synthesized through reductive amination between 2-pyridyl aldehyde and 2-pyridylmethylamine. Other ligands (11, 12, 15, 16) were synthesized by slightly modifying the method known in the document (Kojima, T.; Fukuzumi, S. Chem. Eur. J. 2007, 13, 8212 - 8222). 2-Chloromethylpyridine hydrochloride having various functional groups at position 4 was synthesized by Sn2 reaction with bis-2-pyridylmethylamine (1) at a ratio of 1:1 or Sn2 reaction with 2-pyridylmethylamine at a ratio of 1:2. In addition, No. 13 was synthesized by reducing ester, and No. 14 was synthesized through an aminolysis reaction with an excess of ethylenediamine. Most of the synthesized TPMA ligands have three pyridine rings, so they have strong basicity and cannot be purified by column chromatography using silica, and therefore, they were purified by column chromatography using basic or neutral alumina. 1-1. Bis(2-pyridiylmethyl)amine (1)
NaBH,4 I H NH MeOH -, N rt,4h NN 98% 1 Put 2-pyridylaldehyde (3.0 g, 27 mmol) and 2-aminomethylpyridine (3.0 g, 27 mmol) in a round bottom flask, and then add methanol (25 mL). After stirring at a room temperature for 3 hours, slowly put NaBH4 (3.1 g, 81 mmol) at 0 °C. After completing addition, stir at a room temperature for 4 hours. When it is confirmed that the reaction completely progresses, add 10% hydrochloric acid solution and terminate the reaction. Concentrate the solution using a rotary evaporator, and adjust pH to 9 by adding NaCO3 saturated aqueous solution. After transferring to a separatory funnel, extract the water layer with CH2C2 three times. Thereafter, add anhydrous MgSO4 to the collected organic layer to remove water and filter a desiccant using a glass filter under reduced pressure. Remove the organic solvent using a rotary evaporator. Through this, Product 1 in a yellow oil form was obtained; (5.4 g, 98%); 'H NMR (400 MHz, CDC 3 ) 6 8.57 (d, J= 4.8 Hz, 2H), 7.65 (dd, J= 7.2, 4.8 Hz, 2H), 7.37 (d, J= 7.6 Hz, 2H), 7.17 (d, J= 5.2, 7.2 Hz, 2H), 3.99 (s, 4H)
200043991 (GHMatters) P122101.AU
1-2. 2,4-Diethoxycarbonylpyridine (2)
0 OH 0 OEt
H2 SO4 OH EtOH -OEt N reflux, overnight N 0 97% 0 2
Put 2,4-pyridinedicarboxylic acid (5g, 30 mmol) in a round bottom flask, and then add ethanol (250 mL) to dissolve it. After adding concentrated sulfuric acid (3.28 mL) in a reaction flask, and then install a reflux pipe to stir while refluxing at 80 °C for 24 hours. After cooling the reaction flask to a room temperature, remove ethanol using a rotary evaporator. Add NaCO3 saturated aqueous solution and transfer to a separatory funnel, and then extract the water layer with CH2C2 three times. Thereafter, add anhydrous MgSO4 to the collected organic layer to remove water and filter a desiccant using a glass filter under reduced pressure. Remove the organic solvent using a rotary evaporator. Through this, Product 2 in a white solid form was obtained; (6.5 g, 97%);'H NMR (400 MHz, CDCl3) 6 8.92 (d, J= 5.6 Hz, 1H), 8.65 (s, 1H), 8.04 (d, J= 6.0 Hz, 1H), 4.52 (q, J= 6.4 Hz, 2H), 4.46 (q, J= 5.6 Hz, 2H), 1.48 (t, J= 6.0 Hz, 3H), 1.43 (t, J= 6.0 Hz, 3H)
1-3.4-Ethoxycarbonyl-2-hydroxymethylpyridine(3)
0 OEt 0 OEt
Na H4, CaCl 2 ,
OEt EtOH N -°C,2.5h N 0 64% OH 2 3
Put a starting material (2) (6.0 g, 27 mmol) and NaBH4 (0.664g, 35 mmol) in a round bottom flask and add ethanol (50 mL) to dissolve it. Slowly add CaCl2(3.0 g, 27mmol) in a reaction flask at 0 °C by dissolving in ethanol. After completing addition, stir at 0 °C for 2 hours and 20 minutes. When it is confirmed that the reaction completely progresses, add concentrated sulfuric acid and terminate the reaction. Filter the white precipitate using a glass filter, and concentrate the solution using a rotary evaporator. Add NaCO3 saturated aqueous solution and transfer to a separatory funnel, and then extract the water layer with CH2C2 three 200043991 (GHMatters) P122101.AU times. Thereafter, add anhydrous MgSO4 to the collected organic layer to remove water and filter a desiccant using a glass filter under reduced pressure. Remove the organic solvent using a rotary evaporator. Through this, Product 3 in a yellow solid form was obtained; (3.1 g, 64%); 1H NMR (400 MHz, CDCl3) 6 8.96 (d, J= 5.6 Hz, 1H), 8.42 (s, 1H), 8.34 (d, J= 5.6 Hz, 1H), 5.22 (s, 2H), 4.53 (q, J= 7.2 Hz, 2H), 1.47 (t, J= 6.8 Hz, 3H) 1-4.4-Ethoxycarbonyl-2-chloromethylpyridinehydrochloride(4)
0 OEt 0 OEt SOC12, CHCIa N rt, overnight OH 90% CI~I1 CI 3 4
Put a starting material (3) (2.9 g, 16 mmol) in a round bottom flask and add CH 2C 2
(30 mL) to dissolve it. Slowly add thionyl chloride (9.5 g, 80 mmol) to a reaction flask after diluting it in CH2C12 (15 mL). After completing addition, stir at a room temperature overnight. When it is confirmed that the reaction completely progresses, remove the solvent using a rotary evaporator. Through this, Product 4 in a white solid form was obtained; (3.616 g, %); 'H NMR (400 MHz, CDC 3) 6 8.82 (d, J= 6.0 Hz, 1H), 8.55 (s, 1H), 8.35 (d, J= 6.4 Hz, 1H), 5.24 (s, 2H), 4.54 (q, J= 7.6 Hz, 2H), 1.48 (t, J= 7.2 Hz, 3H) 1-5. 4-Methoxy-2-hydroxymethylpyridine (5) OMe OMe NaBH4, CaCl 2 OMe EtOH N -5'C,2.5h N o 63% OH 5
Put 4-methoxypyridine-2-carboxylate (4.95g, 29 mmol) and NaBH4 (1.45 g, 44 mmol) in a round bottom flask and add ethanol (40 mL) to dissolve it. Slowly add CaCl2(3.28 g, 29 mmol) to a reaction flask at 0 °C by dissolving it in ethanol. After completing addition, stir at -5 °C for 2 hours and 30 minutes. When it is confirmed that the reaction completely progresses, add concentrated sulfuric acid and terminate the reaction. Filter the white precipitate using a glass filter, and concentrate the solution using a rotary evaporator. Add NaCO3 saturated aqueous solution and transfer to a separatory funnel, and then extract the water layer with CH2C2 three times. Thereafter, add anhydrous MgSO4 to the collected 200043991 (GHMatters) P122101.AU organic layer to remove water and filter a desiccant using a glass filter under reduced pressure. Remove the organic solvent using a rotary evaporator. Through this, Product 5 in a white solid form was obtained; (2.14 g, 53%); 1 H NMR (400 MHz, CDCl 3 ) 6 8.37 (d, J= 4.0 Hz, 1H), 6.78 (s, 1H), 6.74 (d, J= 3.2 Hz, 1H), 4.71 (s, 2H), 3.86 (s, 3H) 1-6. 4-Methoxy-2-chloromethylpyridine hydrochloride (6)
OMe OMe SOCl CH 2 Cl 2 N rt, overnight CI OH 95% HI CI
Put a starting material (5) (1.60 g, 11 mmol) in a round bottom flask and add CH2C 2
(20 mL) to dissolve it. Slowly add thionyl chloride (6.83 g, 57 mmol) to a reaction flask after diluting it in CH2C12 (10 mL). After completing addition, stir at a room temperature overnight. When it is confirmed that the reaction completely progresses, remove the solvent using a rotary evaporator. Through this, Product 6 in a white solid form was obtained; (2.11 g, 95%); H NMR (400 MHz, CD3CN) 6 8.42 (d, J= 6.8 Hz, 1H), 7.43 (s, 1H), 7.31 (d, J= 6.4 Hz, 1H), 4.98 (s, 2H), 4.06 (s, 3H) 1-7. 2-(Hydroxymethyl)-4-pyridinecarboxamide (7)
0 GEt 0 N H2 NH 4DH EtOH N rt, 24 h N OH 90% OH 3 7
Put a starting material (3) (1.60 g, 11 mmol) in a round bottom flask and add ethanol (10 mL) to dissolve it. Slowly add 30% ammonia water (30 mL) to a reaction flask. After completing addition, stir at a room temperature for 24 hours. When it is confirmed that the reaction completely progresses, remove the solvent using a rotary evaporator. After that, it was used for the next reaction without an additional purification process. Through this, Product 7 in a white solid form was obtained; (0.78 g, 90%);1 H NMR (400 MHz, DMSO) 8.60 (d, J= 4.0 Hz, 1H), 8.42 (d, J= 4.0 Hz,1H, NH), 7.89 (s, 1H), 7.63(d, J= 4.0 Hz, 1H), 7.53(d, J= 4.0 Hz, 1H, NH 2 ), 4.61 (s, 2H) 1-8. 4-Cyano-2-chloromethylpyridine (8) 200043991 (GHMatters) P122101.AU
0 NH 2 CN soa2 DMF N rt, 12 h OH 70% 7 8 Put a starting material (7) (94 mg, 0.55 mmol) in a round bottom flask and add DMF (3 mL) purified by distillation to dissolve it. Slowly add thionyl chloride (325 mg, 2.8 mmol) to a reaction flask at 0 °C after diluting it in DMF (6 mL). After completing addition, stir at a room temperature for 12 hours. Add NaCO3 saturated aqueous solution to neutralize it, thereby terminating the reaction. After transferring the product of the flask to a separatory funnel, extract the water layer with ethyl acetate three times. Thereafter, wash the organic layer with water until DMF is removed all. Add anhydrous MgSO4 to the collected organic layer to remove water and filter a desiccant using a glass filter under reduced pressure. Remove the organic solvent using a rotary evaporator. Through this, Product 8 in a brown oil form was obtained; (695 mg, 70%); 1H NMR (400 MHz, CDCl 3) 6 7.76 (d, J= 4.8 Hz, 1H), 7.76 (s, 1H), 7.50 (d, J= 4.8 Hz,1H), 4.73 (s, 2H), 13CNMR (100 MHz, CDC3) 6 158.28, 150.32, 124.46, 124.29, 121.47, 116.12 and 45.63 1-9. 2-thiazoylmethylamine (9)
(1) NH 2 H -Ha, NaOH EtOH + H20 0 reflux, 05 h (S NH 2 (2)NH40Ac NaOH,Zn N4HH EtOH reflux, 0.5 h 35% 9
Put NH2 OH-HCl (2.3 g, 30 mmol), 2-thiazolecarboxyaldehyde (2.5 g, 20 mmol), and NaOH (2.6 g, 60 mmol) in a round bottom flask, and add ethanol (20 mL) and distilled water (4 mL) to dissolve it. Install a reflux pipe in a reaction flask and reflux while stirring at 80 °C for 30 minutes. After cooling to a room temperature, add 2N hydrochloric acid to acidify it by pH 4. After transferring the product of the flask to a separatory funnel, extract the water layer with Et20 two times. Thereafter, add anhydrous MgSO4 to the collected organic layer to remove water and filter a desiccant using a glass filter under reduced pressure. Remove the organic solvent using a rotary evaporator. Through this, obtain an intermediate product in a
200043991 (GHMatters) P122101.AU white solid form. Add ethanol (30 mL) and 30% ammonia water (60 mL) to this intermediate product to dissolve it. Add zinc dust (10.1 g, 200 mmol) and ammonium acetate (1.3 g, 20 mmol) in order, and install a reflux pipe and reflux while stirring at 80 °C for 30 minutes. After cooling to a room temperature, filter it using a glass filter. Dilute the filtered solution by adding water and transferring it to a separatory funnel, and then extract it with CH2C2 three times. Thereafter, add anhydrous MgSO4 to the collected organic layer to remove water and filter a desiccant using a glass filter under reduced pressure. Remove the organic solvent using a rotary evaporator. Through this, Product 9 in a yellow oil form was obtained; (0.8 g, %); 1H NMR (400 MHz, DMSO) 6 7.68 (d, J=3.2 Hz, 1H), 7.55 (d, J= 3.2 Hz, 1H), 3.98 (s, 2H), 2.32 (br, 2H)
1-10. Tris(2-pyridiylmethyl)amine (10)
oN
00
Put a starting material (1) (1.05 g, 5.3 mmol) and 2-pyridylaldehyde (0.63 g, 5.3
mmol) in a round bottom flask and add methanol (15 mL). Stir at a room temperature for 2 hours and slowly add NaBH4 (0.61 g, 16 mmol) at 0 °C. When it is confirmed that the reaction
completely progresses, add 10% hydrochloric acid solution and terminate the reaction. Concentrate the solution using a rotary evaporator, and adjust pH to 9 by adding NaCO3 saturated aqueous solution. After transferring to a separatory funnel, extract the water layer
with CH2Cl2three times. Thereafter, add anhydrous MgSO4 to the collected organic layer to remove water and filter a desiccant using a glass filter under reduced pressure. Remove the
organic solvent using a rotary evaporator. After that, purify it by recrystallization with Et20, Product 10 in a colorless crystal form was obtained; (1.2 g, 78%); 1 H NMR (400 MHz,
CDCl3) 6 8.53 (d, J = 4.4 Hz, 3H), 7.65 (dd, J = 5.0, 7.6 Hz, 3H), 7.58 (d, J = 7.6 Hz, 3H), 7.15 (dd, J = 5.6, 7.2 Hz, 3 H), 3.8 8 (s, 6H)
1- 11. 2-(Bis(4,4'-ethoxycarbonyl-2,2'-pyridinyl)methylamino)methylpyridine (11)
200043991 (GHMatters) P122101.AU
0 QEt NH EtO N D S N 2 ¾ Et IN2 2QO"; NA N+ Acetonitrile N ai reflux, 12 h N 65%6J
4 11
Put a starting material (4) (1.0 g, 4.25 mmol), 2-pyridylmethylamine (0.21 g, 1.93 mmol), Na2CO3 (4.5 g, 42.5 mmol) and acetonitrile (20 mL) in a round bottom flask. Install a reflux pipe in a reaction flask and reflux while stirring at 80°C for 12 hours. When the reaction is completed, cool it to a room temperature and then remove an excess of Na2CO3 using a glass filter. Concentrate the solution using a rotary evaporator, and purify a mixture in a dark red oil form by column chromatography by alumina using a developing solution having the composition of hexane : EtOAc = 2 : 5, thereby obtaining Product 11 in a red oil form; (0.55 g, 65%); 1H NMR (400 MHz, CDC 3) 6 8.68 (d, J=5.2 Hz, 2H), 8.54 (d, J= 5.0 Hz, 1H), 8.10 (s, 2H), 7.70 (d, 2H), 7.69 (dd, 1H), 7.60 (d, J=3.6 Hz, 1H), 7.16 (dd, J= 6.0, 7.2 Hz, 1H), 4.42 (q, J= 7.2 Hz, 4H), 3.99 (s, 2H), 3.93 (s, 4H) 1.42 (t, J= 7.2 Hz, 6H) 1-12. 2-(Bis(2-pyridinyl)methylamino)methyl-4-ethoxycarbonylpyridine (12)
0 DEt H NN "0
NNa 2 CO-1 N+ Acetonitrile N N6 reTu, 12h N 82%
4 12
Put a starting material (1) (0.35 g, 1.77 mmol), a staring material (4) (0.5 g, 1.94 mmol), Na2CO3 (2.2 g, 19.4 mmol) and acetonitrile (15 mL) in a round bottom flask. Install a reflux pipe in a reaction flask and reflux while stirring at 80°C for 12 hours. When the reaction is completed, cool it to a room temperature and then remove an excess of Na2CO3 using a glass filter. Concentrate the solution using a rotary evaporator, and purify a mixture in a dark red oil form by column chromatography by basic alumina using acetonitrile as a developing solution, thereby obtaining Product 12 in an orange oil form; (0.53 g, 82%);'H NMR (400 MHz, CDC 3) (8.68 (d, J= 4.8 Hz, 1H), 8.54 (d, J= 4.0 Hz, 2H), 8.12 (s, 1H), 7.69 (d, J= 4.0 Hz, 1H), 7.65 (dd, 2H), 7.60 (d, J= 7.6 Hz, 2H), 7.15 (dd, J= 6.0, 7.2 Hz, 2H), 4.42 (q, J= 6.8 Hz, 2H), 3.96 (s, 2H), 3.89 (s, 4H) 1.42 (t, J= 6.8 Hz, 3H) 1-13. 2-(Bis(2-pyridinyl)methylamino)methyl-4-hydroxymethylpyridine (13) 200043991 (GHMatters) P122101.AU
EtO 0 HO.
NaBH4 N NH 4 N N k EtOH N rt, 12 h 45%
12 13
Put a staring material (12) (100 mg, 0.28 mmol) in a round bottom flask, and then add ethanol (10 mL) to dissolve it. Slowly put NaBH4 (21 mg, 0.84 mmol) at 0 °C and after adding all, stir at a room temperature for 12 hours. After 12 hours, add a saturated ammonium chloride aqueous solution to terminate the reaction. Filter the white precipitate using a glass filter, and concentrate the solution using a rotary evaporator. Add an NaCO 3 saturated aqueous solution and transfer it to a separatory funnel, and then extract the water layer with CH 2 C2 three times. Thereafter, add anhydrous MgSO4 to the collected organic layer to remove water and filter a desiccant using a glass filter under reduced pressure. Remove the organic solvent using a rotary evaporator. Through this, Product 13 in a light yellow oil form was obtained; (40 mg, 45%); 1H NMR (400 MHz, CDC 3) 6 8.51 (d, J= 4.8 Hz, 2H), 8.47 (d, J= 5.2 Hz, 1H), 7.64 (dd, J= 3.6, 4.0 Hz 2H), 7.59 (d, J= 5.2 Hz, 2H), 7.55 (s, 1H), 7.16 (d, J= 5.2 Hz, 1H), 7.13 (dd, J= 3.2, 3.2 Hz, 2H), 4.73 (s, 2H), 3.88 (s, 2H), 3.86 (s, 4H) 1-14.2-(Bis(2-pyridinyl)methylamino)methyl-4-(2-aminoethyl)pyridinecarboxamide (14) H EtO 0 0
N ethylen edia min e |~ N N n eat N N 80 C, 16h
12 14 Slowly add a starting material (12) (1.35 g, 3.7 mmol) to ethylene diamine (22.5 g, 370 mmol) purified by dissolving in a minimum quantity of CH 2C2 in a round bottom flask. Install a reflux pipe in a reaction flask, and stir at 80°C for 16 hours. When the reaction is completed, cool to a room temperature and then pour water 30 mL. After transferring the product of the flask to a separatory funnel, extract the water layer with CH 2C2 three times. Thereafter, add anhydrous MgSO4 to the collected organic layer to remove water and filter a desiccant using a glass filter under reduced pressure. Remove the organic solvent using a rotary evaporator. Through this, Product 14 in a light yellow oil form was obtained; (1.20 g, 200043991 (GHMatters) P122101.AU
86%);'HNMR(400 MHz, CDC 3)8.62(d,J=4.0Hz, 1H), 8.54(d,J= 8.0Hz,2H), 8.23 (s, 1H), 7.64 (dd, J= 8.0, 8.0 Hz, 2H), 7.55 (d, J= 4.0 Hz, 1H), 7.49 (d, J= 8.0 Hz, 2H), 7.43 (br, 1H), 7.15 (dd, J= 6.0, 6.0 Hz, 2H), 3.93 (s, 2H), 3.87 (s, 4H), 3.55 (t, J= 8.0 Hz, 2H), 2.98 (t, J= 8.0 Hz, 2H) 1-15.2-(bis(4,4'-methoxy-2,2'-pyridinyl)methylamino)methylpyridine(15)
OMe - NH 2 OMe N2CO 3 N N acetonitrile N+ reflux 12h N HI CI 60%
6 15
Put a starting material (6) (1.0 g, 5.18 mmol), 2-pyridylmethylamine 0.28 g, 2.59 mmol), Na2CO3 (2.7 g, 25.9 mmol) and acetonitrile (20 mL) in a round bottom flask. Install a reflux pipe in a reaction flask and reflux while stirring at 80°C for 12 hours. When the reaction is completed, cool it to a room temperature and then remove an excess of Na2CO3 using a glass filter. Concentrate the solution using a rotary evaporator, and purify a mixture in a dark red oil form by column chromatography by neutral alumina using acetonitrile as a developing solution, thereby obtaining Product 15 in an orange oil form; (0.54 g, 60%); 1 H NMR (400 MHz, CDC 3 ) 6 8.55 (d, J= 4.8 Hz, 1H), 8.34 (d, J= 5.6 Hz, 2H), 7.64(dd, J= 4.8, 4.4 Hz, 1H), 7.58 (d, J= 4.0 Hz, 1H), 7.21 (s, 2H), 7.15 (dd, J= 5.2, 4.4 Hz, 1H), 6.68 (d, J= 3.2 Hz, 2H), 3.90 (s, 2H), 3.85 (s, 4H) 3.84 (s, 6H) 1-16.2-(bis(4,4'-cyano-2,2'-pyridinyl)methylamino)methylpyridine(16)
CN NH 2 CN Na2CO 3 N acetonitrile N reflux 12 h N cl 58% 16
Put a starting material (8) (54 mg, 0.345 mmol), 2-pyridylmethylamine 17 mg, 0.157 mmol), Na2CO3 (166 mg, 1.57 mmol) and acetonitrile (10 mL) in a round bottom flask. Install a reflux pipe in a reaction flask and reflux while stirring at 80°C for 12 hours. When the reaction is completed, cool it to a room temperature and then remove an excess of Na2CO3 using a glass filter. Concentrate the solution using a rotary evaporator, and purify a mixture in a dark red oil form by column chromatography by neutral alumina using acetonitrile as a 200043991 (GHMatters) P122101.AU developing solution, thereby obtaining Product 16 in a yellow oil form; (36 mg, 68%); 'H NMR (400 MHz, CDC 3 ) 6 8.73 (d, J= 5.2 Hz, 2H), 8.58 (d, J= 4.4 Hz, 1H), 7.80 (s, 2H), 7.70 (dd, J= 6.8, 5.2 Hz, 1H), 7.46 (d, J= 5.2 Hz, 1H), 7.41 (d, J= 4.4 Hz, 2H), 7.20 (dd, J= 7.2, 4.4 Hz, 1H), 3.99 (s, 4H), 3.91 (s, 2H) 1-17.2-(Bis(4,4'-ethoxycarbonyl-2,2'-pyridinyl)methylamino)methylthiazole(17) EtO 0
OEt 4 -S NH2 Na 2 COs N N 0 2 accetc n Rri leI reflux, 36 h N S 57% 9 17
Put a starting material (4) (0.45 g, 1.929 mmol), a starting material (9) (0.1 g, 0.877 mmol), Na2CO3 (2.04 g, 19.3 mmol) and acetonitrile (15 mL) in a round bottom flask. Install a reflux pipe in a reaction flask and reflux while stirring at 80°C for 36 hours. When the reaction is completed, cool it to a room temperature and then remove an excess of Na2CO3 using a glass filter. Concentrate the solution using a rotary evaporator, and purify a mixture in an orange oil form by column chromatography by neutral alumina using acetone as a developing solution, thereby obtaining Product 17 in a yellow oil form; (0.22 g, 57%); 1 H NMR (400 MHz, CDC 3 ) 6 8.69 (d, J= 7.2 Hz, 2H), 8.18 (s, 2H), 7.73 (d, J= 4.0 Hz, 1H), 7.72 (d, J= 7.2 Hz, 2H), 7.31 (d, J= 4.0 Hz, 2H), 4.43 (q, J= 7.2 Hz, 4H), 4.16 (s, 2H), 4.04 (s, 4H), 1.43 (t, J= 7.2 Hz, 6H)
Example 2. Synthesis of TPMA-based osmium complexes From ligands synthesized from Example 1 (1-1 to 1-17), [Os(TPMA)Cl ]*(PF6) 2
complexes and derivatives thereof were synthesized. All the synthesized complexes could be synthesized from ammonium hexachloroosmate. Then, as a step in which an osmium salt in a tetravalent ionic state is reduced to an osmium complex in a trivalent ionic state, after the reaction, precipitation was obtained in an ammonium hexafluorophosphate (NH4 PF 6) aqueous solution to initially obtain all in a form of a complex having PF 6 as a counter ion. This synthesis reaction scheme was shown in FIG. 2.
As all the [Os(TPMA)C 2]*(PF6) complexes have paramagnetic characteristics, it could not be observed by 1 H-NMR. This was because unpaired electrons of the paramagnetic 200043991 (GHMatters) P122101.AU material interact with nuclear spin to shorten the relaxation time. Therefore, for the produced osmium complexes, the synthesis result and oxidation state of the materials were determined through ESI-MS. In addition, the crystal structure of the [Os(TPMA)C 2 ]*(PF6-) (18) complex could be confirmed by Single crystal X-ray diffraction, and this was shown in FIG. 3. By reacting the [Os(TPMA)Cl 2 ]*(PF6-)-based complexes synthesized by an additional step with various monodentate ligands or bidentate ligands, various kinds of osmium complexes were synthesized. The [Os(TPMA)(L)i~2]*(PF6-)-based complexes could be synthesized by reacting the monodentate ligands such as 1-methylimidazole, pyridine and the like, and bidentate ligands such as 4-methyoxy-2-pyridylcarboxyamide, picolinic acid, catechol, acetylacetone and the like with [Os(TPMA)Cl2]*(PF6-) and passing through an exchange reaction with a chloride (Cl) ligand. This synthesis reaction scheme was shown in FIG. 4. As all the synthesized [Os(TPMA)(L)i~2]"(PF6-)n-based complexes have paramagnetic characteristics as same as the [Os(TPMA)Cl 2]f(PF6-) complexes, they could not be observed by 1 H-NMR, and the synthesis result and oxidation state of the materials were determined by ESI-MS. Among the [Os(TPMA)(L)i~2]"(PF6-)n-based complexes, in case of compounds (27 ~ 33) in which oxygen is coordinated, such as catechol, acetylacetone, picolinic acid, and the like, during the reaction, the reaction was carried out by adding a based such as triethylamine (TEA) or sodium hydroxide (NaOH). Among the synthesized TPMA-based complexes, in case of complexes having a hydroxymethyl (-CH 2 H) group in a TPMA ligand such as 21, 31 and 32, a mass signal in which the hydroxy (-OH) group was removed was characteristically removed. This is determined that the mass signal in which the hydroxy group was removed was observed, as a pyridylmethyl (-PyCH2) group with high reactivity is easily ionized and has stability. (FIG. 5) In case of 26, 34 and 35 complexes in which a monodentate ligand, 1 methylimidazole was reacted with [Os(TPMA)Cl2 ]*(PF6-), they could be obtained with high yield when they were reacted under 2 ~ 10 equivalents of 1-methylimidazole and ethylene glycol solvent under the condition of 130 ~ 180 °C, 3 ~ 12 h. However, in case of the
[Os(TPMA)(imi)Cl]"(PF6-)n complex in which only one 1-methylimidazole was coordinated, the reaction was not progressed at all when reacting only 1 equivalent of1-methylimidazole, and when 2 equivalents were added, this could not be selectively obtained, such that 2 of imidazole ligands were coordinated, and the like.
20004399_1 (GHMatters) P122101.AU
All the synthesized TPMA-based osmium complexes were obtained initially in a PF6 counter ion form, and a complex in a [Os(TPMA)Cl ]*(Cl-) 2 or [Os(TPMA)(L)~2]"*(Cl-)n form could be obtained using Cl- ion exchange resin. Most of the TPMA-based osmium complexes showed a large difference in solubility depending on the form of the counter ion. When PF6 was in the form of a counter ion, they showed good solubility in acetonitrile and acetone solvents, but in water and methanol, they showed poor solubility. Conversely, in the Cl counter ion form, they showed good solubility in water and methanol, and they were hardly dissolved in an organic solvent such as acetonitrile and acetone.
2-1. [Os(TPMA)Cl 2]*(PF6) Complex (18)
N (NH4)OSCle] N N N ethylene glycol 0sN (PF8) 140 °C, 6 h C \C\ -N 73% CI
10 18
Put ammonium hexachloroosmate (30 mg, 0.068 mmol) and a starting material (10) (20 mg, 0.068 mmol) in a glass culture tube and add ethylene glycol (2 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 140 °C for 6 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining green solid Product 18 having a counter ion of PF6&. (35 mg, 73%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~1 mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the remaining Cl-resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (Low resolution): Calcd for cation[M]* C 18Hi8Cl 2N 40s: 552.05 Found: 552.16[M]*
2-2. [Os(TPMA)Cl 2]*(PF6) Complex (19)
200043991 (GHMatters) P122101.AU
EtO 0 0 OEt N 0 N N N {NH 4 )[OsC1 6] N ' IEt ethylene glycol ( N s_ Y,, (PF 6 ~ N 140OC.6 h N CI EtO 96% \ CI
0L 11 19
Put ammonium hexachloroosmate (129 mg, 0.293 mmol) and a starting material (11) (120 mg, 0.293 mmol) in a glass culture tube and add ethylene glycol (3 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 140 °C for 6 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining brown solid Product 19 having a counter ion of PF6j. (220 mg, 95%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~1 mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the remaining Cl resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (Low resolution): Calcd for cation[M]* C 24 H2 6 Cl 2N 4 040s: 696.09 Found: 696.25[M]'
2-3. [Os(TPMA)Cl 2 ]+(PF6) Complex (20) EtO
0 OEt N"-1+
N N (NH 4 )[0sCI6 ] Ni Il1] N ethylene lycol Os (PF 6 140 0 C, 6 h /N CI 91% CI
12 20
Put ammonium hexachloroosmate (327 mg, 0.744 mmol) and a starting material (12) (270 mg, 0.744 mmol) in a glass culture tube and add ethylene glycol (3 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass 200043991 (GHMatters) P122101.AU culture tube, and then reflux at 140 C for 6 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining brown solid Product 20 having a counter ion of PF6j. (521 mg, 91%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~1 mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the remaining Cl resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (Low resolution): Calcd for cation[M]* C 2 1 H2 2 Cl 2N 4 02Os: 624.07 Found: 624.25[M]*
2-4. [Os(TPMA)Cl2]+(PF6) Complex (21) OH
OH / 1+
N (NH4)[OsCle] N] N .. g (PFe) N ethylene glycol OsP 140 C, 6 h /N CI IN 50% CI
13 21
Put ammonium hexachloroosmate (62 mg, 0.141 mmol) and a starting material (13) (45 mg, 0.141 mmol) in a glass culture tube and add ethylene glycol (3 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 140 C for 6 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining brown solid Product 21 having a counter ion of PF6j. (51 mg, 50%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~1 mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the remaining Cl-resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (Low resolution): Calcd for cation[M]* C 19H2 0Cl 2N400s: 582.06 Found: 566.2500[M-OH]*
200043991 (GHMatters) P122101.AU
2-5. [Os(TPMA)Cl 2 ]+(PF6) Complex (22) NH 2 H
0 NH N -1+12+
N (NH 4 )[OsC16] N N N ethylene glycol s N (PF 6 ) 112 140 C, 16 h /N CI N CIl
14 22 Put ammonium hexachloroosmate (326 mg, 0.742 mmol) and a starting material (14) (280 mg, 0.742 mmol) in a glass culture tube and add ethylene glycol (3 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 140 °C for 6 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining brown solid Product 22 having a counter ion of PF6j. (355 mg, 61%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~1 mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the remaining Cl resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (High resolution): Caled for cation[M]* C 2 1 H2 4 Cl 2N 600s: 638.10 Found: 638.0998[M]*, 319.5538[M] 2 +
2-6. [Os(TPMA)Cl 2 ]+(PF6) Complex (23) OMe
N (NH 4 )[OsCIl] N I )
N ethylene glycol Os N 140OC, 6 h Cl 95 % CI MeO- 15 23
200043991 (GHMatters) P122101.AU
Put ammonium hexachloroosmate (129 mg, 0.293 mmol) and a starting material (15) (120 mg, 0.293 mmol) in a glass culture tube and add ethylene glycol (3 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 140 °C for 6 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining brown solid Product 23 having a counter ion of PF6j. (220 mg, 95%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~1 mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the remaining Cl resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (Low resolution): Calcd for cation[M]* C 20 H22 Cl 2N 4 02Os: 612.07 Found: 612.16[M]*
2-7. [Os(TPMA)(L)1~ 2 ]"*(PF6&)n Complex (24) 1+ MeO -1+12+ 0 \NN N N NH2 N ll S-(PFe)- 1 Os. ethylene glycol s NH \ 'cI 130OC, 12 h CI /
40%
OMe 18 24
Put a starting material (18) (60 mg, 0.086 mmol) and 4-methoxy-2 pyridinecarboamide (65 mg, 0.430 mmol) in a glass culture tube and add ethylene glycol (3 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 130 °C for 12 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining brown solid Product 24 having a counter ion of PF6&. (32 mg, 40%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~1 mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the 200043991 (GHMatters) P122101.AU remaining Cl-resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (Low resolution): Caled for cation[M]* C2 5 H2 6N 6 02Os: 634.17 Found: 634.2500[M]', 2 317.1667[M] +
2-8. [Os(TPMA)(L)1~ 2 ]"*(PF6&)n Complex (25) - 1+ 1 -- 2+ INI
OsN N (PI-3y)- ethylene glycol Os N (PFe)-2 N\ Cl 130D°C, 3 h N N Cl I N N
18 25 Put a starting material (18) (30 mg, 0.043 mmol) and N-methylimidazole (35 mg, 0.430 mmol) in a glass culture tube and add ethylene glycol (1.5 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 130 °C for 3 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining brown solid Product 25 having a counter ion of PF6j. (34 mg, 85%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~1 mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the remaining Cl-resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (Low resolution): Calcd for cation[M]* C2 6H3 oN 8Os: 646.22 Found: 323.08[M] 2 +
2-9. [Os(TPMA)(L)1~ 2]1"(PF6)n Complex (26)
200043991 (GHMatters) P122101.AU
1+ 1+
N N N " -IINI F |N- NN (PFg) N I | Os. ethylene glycol \ Os N CI 180'C, 15 h N N Cl 29%
18 26
Put a starting material (18) (100 mg, 0.143 mmol) and pyridine (11 mg, 0.143 mmol) in a glass culture tube and add ethylene glycol (4 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 180 °C for 15 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining brown solid Product 26 having a counter ion of PF6&. (31 mg, 29%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~1 mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the remaining Cl-resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (Low resolution): Calcd for cation[M]* C23H23ClNOs: 596.13 Found: 596.3333[M]*
2-10. [Os(TPMA)(L)~ 2]"*(PF6&)n Complex (27) Br\- -1
- N _N/ -1+OH N N /I NC triethylarmine OS (PF6) (PFrr H2 0 / N'\-0 /N 100 C,3h N CI1 76%_
Br 18 27
Put a starting material (18) (100 mg, 0.143 mmol) and 4-bromopicolinic acid (173 mg, 0.861 mmol), and triethylamine (145mg, 1.430mmol) in a glass culture tube and add distilled water (3 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 100 °C for 3 hours. Slowly drop 200043991 (GHMatters) P122101.AU the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining brown solid Product 27 having a counter ion of PF6J. (89 mg, 75%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~1 mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the remaining Cl-resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (Low resolution): Caled for cation[M]* C24H21BrN 5 02Os: 682.05 Found: 682.1667[M]'
2-11. [Os(TPMA)(L)~2]"*(PF6&)n Complex (28)
HO)/ N K2 C0 3 N- II Os (PFeH Os N (PFe) CI 100 C, 12 h N' CI 62%
18 28
Put a starting material (18) (30 mg, 0.043 mmol) and catechol (47 mg, 0.430 mmol), and K2C03 (59mg, 0.430mmol) in a glass culture tube and add distilled water (1.5 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 100 °C for 12 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining black solid Product 28 having a counter ion of PF6&. (19.6 mg, 62%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~A mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the remaining Cl-resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (Low resolution): Calcd for cation[M]* C24H22N402Os: 590.14 Found: 590.2500[M]* 2-12. [Os(TPMA)(L)~ 2]"*(PF6&)n Complex (29)
200043991 (GHMatters) P122101.AU
N IN OH N IN Os 6~ (F N triethylamine (PF6) N-~ s ethylene giycol N 0 /N ci 14 0 °C,3h N 0 CI 53%
18 29
Put a starting material (18) (200 mg, 0.287 mmol) and 4-bromopicolinic acid (70 mg, 0.569 mmol) and triethylamine (29mg, 0.287mmol) in a glass culture tube and add ethylene glycol (3 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 140 °C for 3 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining brown solid Product 29 having a counter ion of PF6j. (113 mg, 53%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~1 mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the remaining Cl-resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (High resolution): Cald for cation[M]* C24H22N5 O2Os: 604.14 Found: 604.13824[M]' 2-13. [Os(TPMA)(L)~ 2]"*(PF6&)n Complex (30) 1+ -1+/2+
IN IN IN NaOH IN O Os N (PF6)Y H 20 (PF6)Y 1/2
N \CI 100 C 4 h CI 50%
18 30
Put a starting material (18) (30 mg, 0.043 mmol) and acetylacetone (43 mg, 0.430 mmol), and NaOH (8mg, 0.215mmol) in a glass culture tube and add distilled water (1.5 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 100 °C for 4 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the 200043991 (GHMatters) P122101.AU solution and wash it with distilled water and diethyl ether, thereby obtaining black solid Product 30 having a counter ion of PF6&. (16 mg, 50%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~1 mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the remaining Cl-resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (Low resolution): Caled for cation[M]* C2 3 H2 5N402Os: 581.16 Found: 581.3333[M]*, 2 290.6666[M] +
2-14. [Os(TPMA)(L)~ 2]"*(PF6K)n Complex (31) OH OH
-- 1+ - - 0\
+ N OH N N (P'I)_ triethylarnmne N (P (PFpJ VW 0N- PF ethylene <glycol 0 / C 140°C,4h N CI 51% N 0
21 31
Put a starting material (21) (100 mg, 0.137 mmol) and picolinic acid (67 mg, 0.548 mmol) and triethylamine (56mg, 0.548mmol) in a glass culture tube and add ethylene glycol (3 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 140 °C for 4 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining brown solid Product 31 having a counter ion of PF6&. (54 mg, 51%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (-~ mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the remaining Cl-resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (Low resolution): Calcd for cation[M]* C2 5 H24N 5 O3 Os: 634.15 Found: 618.3333[M-OH] 2-15. [Os(TPMA)(L)~ 2]n'(PF6K)n Complex (32)
200043991 (GHMatters) P122101.AU
- 1+ 0 1+ N N OH N Nj {PF6)_ triethylamine NN (PF 6
) xP Os ethylene glycol Os /N C 140 DC, 4 h N/ CI 53%
21 32
Put a starting material (21) (100 mg, 0.137 mmol) and 4-methylpicolinic acid (76 mg, 0.550 mmol) and triethylamine (56mg, 0.550mmol) in a glass culture tube and add ethylene glycol (3 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 140 °C for 4 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining brown solid Product 32 having a counter ion of PF6j. (58 mg, 53%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~1 mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the remaining Cl-resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (Low resolution): Calcd for cation[M]* C2 6H2 6N 503Os: 648.17 Found: 632.4167[M-OH]* 2-16. [Os(TPMA)(L)~ 2]"*(PF6&)n Complex (33) H H H2N N 0 H 2N N o /-14 - -1+12+
-N OH NN(P e)- triethylamine N N P) (PFe -N_ P4<N~ j2 OS (P~e) ethylene glycoI Oss /N CI 120OC, 6 h N CI 28% N/ 0
22 33
Put a starting material (22) (40 mg, 0.051 mmol) and 4-methylpicolinic acid (28 mg, 0.204 mmol) and triethylamine (15 mg, 153mmol) in a glass culture tube and add ethylene
200043991 (GHMatters) P122101.AU glycol (3 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 120 °C for 5 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining brown solid Product 33 having a counter ion of PF6j. (12 mg, 28%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~1 mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the remaining Cl-resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (High resolution): Calcd for cation[M]* C2 8 H 30 N 7 03Os: 704.20 Found: 704.2019[M]*, 352.6044[M] 2 +
2-17. [Os(TPMA)(L)~ 2]"*(PF6&)n Complex (34) H H H2N N 0 H 2N __N -1+/ 2+ 2+ N NN NN N| S (PF6) 1,N (PFE)-2 Os ethylene glycol Os N CI 130 OC 3 h / N Cl 96% N [N N N
22 34
Put a starting material (22) (40 mg, 0.051 mmol) and N-methylimidazole (42 mg, 0.510 mmol) in a glass culture tube and add ethylene glycol (2 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 130 °C for 3 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining brown solid Product 34 having a counter ion of PF6J. (50 mg, 96%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~1 mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl ion exchange resin, and stir overnight. Filter the remaining Cl-resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product 200043991 (GHMatters) P122101.AU in which a counter ion is Cl-. ESI-MS (High resolution): Calcd for cation[M]* C2 9H36NioOOs: 2 732.27 Found: 367.1182[M+2]
+ 2-18. [Os(TPMA)(L)~ 2]"*(PF6&)n Complex (35) OMe OMe -1+ 2-' IN N NNNO | OsN ethylene glycol'N (PI) 2 N CI 130OC, 3 h / N CI 80% N - -j - z N _
23 35
Put a starting material (23) (30 mg, 0.040 mmol) and N-methylimidazole (32 mg, 0.400 mmol) in a glass culture tube and add ethylene glycol (1.5 mL) to make a mixed solution. Then, blow argon gas for 10 minutes to create an argon atmosphere in the glass culture tube, and then reflux at 130 °C for 3 hours. Slowly drop the solution in which the reaction was completed into a saturated solution, by adding an excess of ammonium hexafluorophosphate to distilled water. Filter the precipitate generated in the solution and wash it with distilled water and diethyl ether, thereby obtaining brown solid Product 35 having a counter ion of PF6j. (31 mg, 80%) To convert the counter ion to Cl-, dissolve the PF6 product in a small amount (~1 mL) of acetonitrile, and then make an excess of distilled water (25 mL) mixture with Cl- ion exchange resin, and stir overnight. Filter the remaining Cl-resin and collect the filtrate, and remove the solvent using distillation under reduced pressure, thereby obtaining a product in which a counter ion is Cl-. ESI-MS (Low resolution): Calcd for cation[M]* C2 8 H3 4N 8 02Os: 706.24 Found: 353.2500[M] 2 +
Example 3. Analysis of electrochemical properties of TPMA-based osmium complexes according to the present invention In order to analyze electrochemical properties of the synthesized TPMA-based osmium complexes, cyclic voltammetry (CV) was used. A well-washed carbon glass electrode with a diameter of 3mm was used as a working electrode, and an Ag/AgC electrode was used as a reference electrode, and a Pt electrode was used as a counter electrode to measure it at a scanning rate of 10 mV/s. The complex in a PF6 counter ion form was measured in an acetonitrile solution of TBAP of 0.1M at a concentration of 3 mg/mL. In order 200043991 (GHMatters) P122101.AU to find out only the position of the redox peak, the complex in a Cl- counter ion form was measured in condition that the concentration of each substance was not constant, by measuring the Cl-substance in a solution state during the anion exchange process. The oxidation-reduction potentials of all the synthesized TPMA-based osmium complexes were shown in FIGs. 7a to c. [Os(TPMA)Cl 2]*(Cl-) (18) is the most basic TPMA osmium complex without any substituent, and exhibited an oxidation-reduction potential of E 1/2 = -0.339 V, and this result was shown in FIG. 6. The change in the oxidation-reduction potential according to the type of the substituent and coordinated ligand was analyzed centering on the present complex. Oxidation/reduction potentials were compared with Complexes Nos. 19 ~ 23 each other, which have a similar coordination structure to Complex No. 18 and comprise different substituents, respectively. Complexes comprising an electron withdrawing group (EWG) such as Complex No. 19 comprising 2 ethylester (-COOEt) groups and Complex No. 20 comprising one and Complex No. 22 comprising an amide (-COONH) group showed more positive values than the oxidation-reduction potential of Complex No. 18. On the other hand, complexes comprising an electron donating group (EDG) such as No. 21 comprising a methyl (-CH2-) group and No. 23 comprising 2 methoxy (-OMe) groups were observed in a more negative value. This result shows that EWG decreases the electron density of the central metal and the potential shifts in the positive direction due to the tendency for reduction, while EDG increases the electron density and the potential appears in a more negative direction due to the tendency to oxidize well. Complexes Nos. 20, 22 moved in a positive direction by about 0.102 ~ 0.103 V than the oxidation-reduction potential of Complex No. 18, and both complexes showed similar oxidation-reduction potentials, indicating that the ester group comprising a carbonyl group and the amide group had similar electrochemical effects. Complex No. 19 shifted in a positive direction by about 0.176 V than the oxidation-reduction potential of Complex No. 18, and it was confirmed that the more EWG there was, the greater the electrochemical effect. Complex No. 21 comprising a hydroxymethyl group slight shifted in a negative direction by 0.031 V, and Complex No. 23 comprising 2 methoxy group, which is a better EDG, shifted in a negative direction by 0.125 V, and therefore, it was judged to have a greater effect according to the kind and number of the EDG. Through this result, it is possible to change the potential of the TPMA-based osmium complexes depending on the
20004399_1 (GHMatters) P122101.AU substituent, and through this, the possibility of application and improvement as an electron transfer mediator with an ideal oxidation-reduction potential was confirmed. Os(TPMA)(L)i~2]"(PF6-)n-based complexes (24 ~ 30) coordinated with various ligands all showed an increased oxidation-reduction potential in a positive direction than Complex No. 18. In order of acetylacetone, 1 pyridine, 4-bromopicolinic acid, picolinic acid, 2 of 1-methylimidazole, 4-methoxy-2-pyridylcarboxyamide, and catechol, the oxidation-reduction potential showed a large increase in a positive direction. Complexes No. , 28 in which 4-methoxy-2-pyridylcarboxyamide and catechol were coordinated, respectively, showed two or more reversible oxidation-reduction peaks, and did not exhibit a single stable oxidation-reduction potential, and thus, they were judged to be unsuitable as an electron transfer mediator. However, since the picolinic acid-coordinated TPMA osmium compound exhibited an ideal oxidation-reduction potential close to 0 V with respect to the Ag/AgC1 electrode, as the potential value shifted in a moderately positive direction, it was judged to be an appropriate TPMA-based osmium complex with potential to be applied to an electron transfer mediator. In addition, characteristically, [Os(TPMA)C2]*(X-)-based Complex 18 ~ 23 showed almost similar redox potentials under a solvent condition different each other according to the counter ion form, but except for these, all [Os(TPMA)(L)~2]"(X ),-based complexes showed oxidation-reduction potentials in a more negative region from a small 36 mV to a large 210 mV in the Cl- counter ion form than the PF6- counter ion form.
20004399_1 (GHMatters) P122101.AU
Claims (16)
- [CLAIMS][Claim 1]A transition metal complex comprising a tetradentate nitrogen donor ligand represented by Chemical formula 1 or 2 below, useful as an electron transfer mediator:[Chemical formula 1]R1 -mCa ~N R3N nX/Lm2_R2[Chemical formula 2]R1 -mCa T ~N R3N" nX M N Lb Cb Lb _R2in the Chemical formula 1 or Chemical formula 2, M is one selected from the group consisting of Fe, Co, Ru, Os, Rh and Ir; and Ca, Cb, Cc are heterocyclic compounds comprising one or more nitrogen atoms, and are preferably linked to an amine group and a methylene group at the position 2 of the cyclic compound; and L" and L2 are monodentate ligands coordinated each independently; and Lb is a bidentate ligand comprising nitrogen or oxygen; and m is a negative charge or positive charge showing -1- -5 or 1 - 5; and20004399_1 (GHMatters)P122101.AUR1, R2 and R3 are each independently a structure composed of a linker into which a reactive group capable of linking to a polymer is introduced; and X is a counter ion; and n means the number of counter ions, and is 1 - 5.
- [Claim 2]The transition metal complex according to claim 1, wherein the transition metal complex comprises a tetradentate ligand represented by Chemical formula 3 below:[Chemical formula 3]NNNin the formula, Ca, Cb and Cc are heterocyclic compounds comprising one or more nitrogen atoms; and R1, R2 and R3 are each independently a linker into which a reactive group capable of linking to a polymer is introduced.
- [Claim 3]The transition metal complex according to claim 2, wherein the tetradentate ligand of the Chemical formula 3 is one of ligands having the following structure:200043991 (GHMatters) P122101.AUHEtO N N H H 2N 2N N N N N N 1 I N N N N 0 N_ N'NNN N NI N N 1 10 1 12 13 N eN NO CNt Et N N NOBNCN N 1 EtO 0 N N O OMM e~ N N N t N N N- NI N'S1N 17,and
- [Claim 4]The transition metal complex according to claim 1 or claim 2, wherein the Ri, R2and R3of the Chemical formulas 1 to 3 are each independently -H; -F; -Cl; -Br; -I; -N02; -CN; -CO 2 H; -SO 3H; -NHNH 2 ; -SH; -OH; -NH 2; -CH2OH; CONHCH 2CH2NH 2; or substituted or unsubstituted alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxy, alkylamino, dialkylamino, alkanylamino, arylcarboxyamido, hydrazino, alkylhydrazino, hydroxyamino, alkoxyamino, alkylthio, alkenyl, aryl or alkyl.
- [Claim 5]The transition metal complex according to claim 1, wherein the L" andL2are each independently -H, -F, -Cl, -Br, -I, -N02,-NCCH 3, -CO, OH2 , -NH3 or a heterocyclic compound comprising one or more nitrogen atoms.
- [Claim 6]The transition metal complex according to claim 1, wherein the Lb- Lbis catechol, acetylacetone, 2-picolinic acid, 2-pyridinecarboxamide, 2,2 bipyridine or 2,2-bithiazole.200043991 (GHMatters) P122101.AU
- [Claim 7]The transition metal complex according to claim 5, wherein the heterocyclic compound may be one or more kinds selected from the group consisting of imidazole, pyridine, pyrimidine, pyrazole, isoxazole, oxazole, thiazole, benzothiazole, benzimidazole, benzoxazole and diazafluorenone.
- [Claim 8]The transition metal complex according to claim 1, wherein the transition metal complex of the Chemical formula 1 or 2 is one of the following transition metal complexes:20004399_1 (GHMatters) P122101.AU complex No. Chemical structure of transition metal complex 18 - +N/N' CI19 EtO 0 - -- 1+ 0 N (X -N Os / N 11 C20 EtO ON 1+N21 OHN - N (X-)C cl20004399_1 (GHMatters) P122101.AU22 H H2 N^ N o 1+NN24 1+/- 0024 1+2+NO Os- Xl1 2N' Os (X)b9N__ _ _2004391GH~ttrsP1210.A27 1+N (X-)N_028 -- iNN0 J-29 1+N NK/O30 -1+12+N (X}/l 231 OH - - 1+NNH P20004399_1 (GHMatters) P122101.AU32 OH 1+IN"N 033 H H 2 N~~N/l 1 V 034H*N. a (XT) 2- N 01\ <\1 ,jN\ 35 DMe - -2+6N MN_______________ N20004399_1 (GHMatters)P122101.AU
- [Claim 9]A method for preparation of the transition metal complex of Chemical formula 1 or 2 according to claim 1, comprising a) introducing a tetradentate tris-pyridinemethylamine-based ligand represented by Chemical formula 3 into an ammonium salt of halogenated osmium of Chemical formula 5, to synthesize an osmium complex of Chemical formula 6; and b) introducing one kind or 2 kinds of monodentate ligands or bidentate ligands selected from the group consisting of N-N ligands, N-ligands, N-0 ligands and 0-0 ligands into the osmium complex of Chemical formula 6:[Chemical formula 3] R NqR2 NN C[Chemical formula 5][(NH4)20sCl][Chemical formula 6] - N -mN- Os -CI dX-N C I_in the formula,Ca, Cband Cc are each independently a heterocyclic compound comprising one or more nitrogen atoms; and R 1, 2 and R3 are each independently a linker into which a reactive group capable of linking to a polymer is introduced.200043991 (GHMatters) P122101.AU
- [Claim 10]The method according to claim 9, wherein in the step b), 1 N-N ligand, 2 N ligands, 1 N ligand, 1 N-0 ligand or 10-0 ligand is introduced into the osmium complex of Chemical formula 6 to prepare a transition metal complex of Chemical formula 7 or 10 below:[Chemical formula 7]N--N-N 'dXI N/ \N)[Chemical formula 8] N . N N[Chemical formula 9]N Os N -dXN CI[Chemical formula 10]N---- dXS/ \ )[Chemical formula 11]N- s -N x
- [Claim 11]The method according to claim 10,200043991 (GHMatters) P122101.AUWherein the N ligand is -NO 2 , -NCCH 3, -NH 3 or a heterocyclic compound comprising one or more nitrogen atoms, andthe N-N ligand is 2-pyridinecarboxamide, 2,2'-bipyridine or 2,2'-bithiazole, and the N-O ligand is 2-picolinic acid, and the 0-0 ligand is catechol or acetylacetone.
- [Claim 12]A device comprising the transition metal complex according to any one claim of claim 1 to claim 8 as an electron transfer mediator.
- [Claim 13]The device according to claim 12, wherein the device is an electrochemical biosensor.
- [Claim 14]The device according to claim 12, wherein the device is an insertable device.
- [Claim 15]A sensing layer for an electrochemical biosensor comprising an enzyme capable of redoxing a liquid biological sample; and the transition metal complex according to any one claim of claim 1 to claim 8 as an electron transfer mediator.
- [Claim 16]The sensing layer according to claim 15, wherein the enzyme comprises one or more kinds of oxidoreductases selected from the group consisting of dehydrogenase, oxidase, and esterase; or one or more kinds of oxidoreductases selected from the group consisting of dehydrogenase, oxidase, and esterase, and one or more kinds of cofactors selected from the group consisting20004399_1 (GHMatters) P122101.AU of flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide (NAD), and pyrroloquinoline quinone (PQQ).20004399_1 (GHMatters) P122101.AU
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2020-0189139 | 2020-12-31 | ||
KR1020200189139A KR20220096569A (en) | 2020-12-31 | 2020-12-31 | Transition metal complex comprising tetradentate Nitrogen donor ligand and electrochemical biosensor comprising the same |
PCT/KR2021/020070 WO2022145982A1 (en) | 2020-12-31 | 2021-12-28 | Transition metal complex containing tetradentate nitrogen donor ligand and electrochemical biosensor comprising same |
Publications (1)
Publication Number | Publication Date |
---|---|
AU2021415745A1 true AU2021415745A1 (en) | 2023-07-13 |
Family
ID=82260701
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2021415745A Pending AU2021415745A1 (en) | 2020-12-31 | 2021-12-28 | Transition metal complex containing tetradentate nitrogen donor ligand and electrochemical biosensor comprising same |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP4273152A1 (en) |
JP (1) | JP2024505810A (en) |
KR (1) | KR20220096569A (en) |
CN (1) | CN117015547A (en) |
AU (1) | AU2021415745A1 (en) |
WO (1) | WO2022145982A1 (en) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8070934B2 (en) * | 2001-05-11 | 2011-12-06 | Abbott Diabetes Care Inc. | Transition metal complexes with (pyridyl)imidazole ligands |
US9533297B2 (en) * | 2012-02-23 | 2017-01-03 | Carnegie Mellon University | Ligands designed to provide highly active catalyst complexes |
-
2020
- 2020-12-31 KR KR1020200189139A patent/KR20220096569A/en not_active Application Discontinuation
-
2021
- 2021-12-28 WO PCT/KR2021/020070 patent/WO2022145982A1/en active Application Filing
- 2021-12-28 CN CN202180094860.4A patent/CN117015547A/en active Pending
- 2021-12-28 AU AU2021415745A patent/AU2021415745A1/en active Pending
- 2021-12-28 EP EP21915780.7A patent/EP4273152A1/en active Pending
- 2021-12-28 JP JP2023540608A patent/JP2024505810A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
CN117015547A (en) | 2023-11-07 |
JP2024505810A (en) | 2024-02-08 |
WO2022145982A1 (en) | 2022-07-07 |
KR20220096569A (en) | 2022-07-07 |
EP4273152A1 (en) | 2023-11-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4420899B2 (en) | Transition metal complexes with (pyridyl) imidazole ligands | |
AU2019341169B2 (en) | Oxidation-reduction polymer including transition metal complex, and electrochemical biosensor using same | |
Kaul et al. | Molybdenum (VI)-dioxo, molybdenum (V)-oxo, and molybdenum (IV)-oxo complexes with 2, 3: 8, 9-dibenzo-1, 4, 7, 10-tetrathiadecane. Models for the molybdenum binding site of the molybdenum cofactor | |
AU2020409909B2 (en) | Novel transition metal electron transfer complex having C-N ligand and electrochemical bio sensor using same | |
KR102352758B1 (en) | Novel redox polymer comprising transition metal complex and Electrochemical biosensor using the same | |
KR20190143644A (en) | Novel Ruthenium-based electron transfer mediator, preparation method thereof, redox reagent composition and biosensor comprising the same | |
AU2021415745A1 (en) | Transition metal complex containing tetradentate nitrogen donor ligand and electrochemical biosensor comprising same | |
US20240158426A1 (en) | Transition metal complex containing tetradentate nitrogen donor ligand and electrochemical biosensor comprising same | |
Albrecht et al. | Redox active donor-substituted punicin derivatives | |
EP4273181A1 (en) | Polymer comprising pentafluorophenyl ester and electrochemical biosensor comprising same | |
EP4328232A1 (en) | Electrochemical biosensor, or sensing membrane for electrochemical biosensor containing transition metal complex or oxidation-reduction polymer | |
KR102596519B1 (en) | Reagent composition for oxdiation reduction reaction and biocensor comprising the same | |
JP7411094B2 (en) | Novel organic electron transfer mediator and device containing same | |
AU2007231899B2 (en) | Transition metal complexes with (pyridyl)imidazole ligands | |
MOTONAKA et al. | Evaluation of Kinetic Parameters of Bipyridine Type Osmium Complexes for Enzyme Reactions | |
AU2011239358A1 (en) | Transition metal complexes with (pyridyl)imidazole ligands |